The invention relates to (+ / -)-guaiacol-based glycerol-beta-O-4apos and a preparation method thereof. Synthesis method of-dihydroconiferyl alcohol
Through the esterification and hydrogenation reduction of ferulic acid and alcohol compounds, combined with benzyl protection, bromination and substitution reactions, (±)-guaerosol-β-O-4'-dihydrogenocide alcohol was successfully achieved. The efficient synthesis of the system solves the problem of low natural extraction yield and provides important drugs for osteoporosis research.
Patent Information
- Application Number
- CN202310766948.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-06-27
- Publication Date
- 2024-12-27
AI Technical Summary
The prior art is difficult to efficiently synthesize erythrone-guaifeniglycerol-β-O-4'-dihydrogenocide alcohol for the treatment of osteoporosis. It has a low natural extraction yield and is difficult to meet the needs of drug research.
Ferulic acid and alcohol compounds are used for esterification and catalytic hydrogenation reduction, followed by benzyl protection, bromination, substitution reaction and reduction, and finally debenzyl protection, achieving (±)-guaerosol-β- Synthesis of O-4′-dihydrogenated cypress alcohol.
This method achieves the efficient synthesis of (±)-Guaizoliglycerol-β-O-4'-dihydrogenocide alcohol. The raw materials are easy to obtain, simple to operate, suitable for industrial production, and provides drug research for osteoporosis. important compounds.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a method for synthesizing (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol. Background Art
[0002] Osteoporosis is a systemic metabolic bone disease and a common disease in the elderly. With the development of society, my country's population structure has also undergone great changes, and the trend of population aging is getting faster and faster. Osteoporosis and its related symptoms are seriously threatening the health of the middle-aged and elderly, especially the health of women. Traditional Chinese medicine has been used to treat fractures and bone and joint diseases for thousands of years, and elderberry has a long history of being used to treat bone diseases. Studies have reported that elderberry extracts show a strong effect in promoting osteoblast proliferation, and dozens of lignan small molecule compounds have been isolated. Erythro-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol is one of the molecules, and its structural formula is as follows:
[0003]
[0004] Osteoblast proliferation experiments showed that erythro-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol has good osteoblast proliferation activity but no estrogen-like side effects. Preliminary studies on its mechanism of action suggest that the compound can regulate the OPG / RANKL / RANK system and protect bones by inhibiting the occurrence of osteoclasts. In addition, the estrogen receptor antagonist ICI182780 can block the compound's effect on osteoblast-like cell proliferation. Therefore, it is believed that the effect of the compound on osteoblast-like cells is achieved through the estrogen action pathway, and the activity of the compound is exerted in an ERE and AP-1 site-independent manner. The specific pathway of action needs further study.
[0005] Using erythro-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol as a lead compound for drug development and drug mechanism research, the hope of obtaining drugs for the treatment of osteoporosis is the current direction of medicinal chemists' efforts. However, the content of erythro-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol in elderberry plants is low, and the yield obtained by extraction is only about 0.007%, which is difficult to meet the needs of drug research. Chemical synthesis methods are efficient and rapid. Finding a chemical synthesis method to quickly and efficiently obtain erythro-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol compounds is of great significance for osteoporosis drug research. Summary of the invention
[0006] In view of this, the technical problem to be solved by the present invention is to provide a method for synthesizing (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol, which has readily available raw materials, simple operation, mild conditions and is easy to industrialize.
[0007] To achieve the above object, the present invention provides a method for synthesizing (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol, comprising the following steps:
[0008] (1) subjecting ferulic acid to an esterification reaction with an alcohol compound in the presence of a catalyst to prepare compound 2;
[0009] (2) subjecting compound 2 to a catalytic hydrogenation reduction reaction to prepare compound 3;
[0010] (3) benzyl protecting compound 4 to prepare compound 5;
[0011] (4) reacting compound 5 with carbonate to prepare compound 6;
[0012] (5) treating compound 6 with a brominating agent to carry out a bromination reaction to prepare compound 7;
[0013] (6) Compound 3 and Compound 7 are mixed to carry out a substitution reaction to prepare Compound 8;
[0014] (7) subjecting compound 8 to a reduction reaction to prepare compound 9;
[0015] (8) Compound 9 was debenzylated to prepare (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol.
[0016] The reaction equation of the above synthesis method is as follows:
[0017]
[0018] The invention uses compound 3 and compound 7 as raw materials to carry out reaction, and then carries out reduction and deprotection to prepare (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol.
[0019] The preparation process of compound 3 includes:
[0020] The ferulic acid (compound 1) and an alcohol compound are subjected to an esterification reaction under the catalysis of a catalyst to prepare compound 2, and then compound 2 is subjected to a catalytic hydrogenation reduction reaction in an organic solvent to prepare compound 3.
[0021] In the step (1), the alcohol compound is preferably a C1-C6 monohydric alcohol; more preferably methanol or ethanol.
[0022] The catalyst in step (1) is preferably one or more of sulfuric acid, hydrogen chloride, thionyl chloride, acetyl chloride, and oxalyl chloride; more preferably thionyl chloride.
[0023] The mass volume ratio of the ferulic acid, the alcohol compound and the catalyst is preferably 1 g: (1-10) mL: (0.5-2) mL.
[0024] The temperature of the esterification reaction is preferably 0-80° C., and the time is preferably 1-10 h.
[0025] In the step (2), the solvent for the catalytic hydrogenation reduction reaction is preferably one or more of methanol, ethanol, ethyl acetate and dichloromethane.
[0026] The catalyst for the catalytic hydrogenation reduction reaction is preferably one or more of palladium carbon, palladium hydroxide carbon, and Raney nickel.
[0027] The molar ratio of the compound 2 to the catalyst is preferably 1:(0.05-0.1).
[0028] The temperature of the catalytic hydrogenation reduction reaction is preferably 20-30° C., the reaction time is preferably 1-10 h, and the hydrogen pressure is preferably 15-30 psi.
[0029] The preparation process of compound 7 includes:
[0030] Compound 4 is reacted with a benzyl halide in an organic solvent under alkaline conditions to carry out benzyl protection to prepare compound 5;
[0031] Compound 5 reacts with carbonate in an organic solvent under alkaline conditions to prepare compound 6;
[0032] Compound 6 is reacted with a brominating agent in an organic solvent to undergo bromination reaction to prepare compound 7.
[0033] In the step (3), the reaction solvent for benzyl protection is preferably one or more of dichloromethane, tetrahydrofuran, acetone, acetonitrile, 1,2-dichloroethane, 1,4-dioxane, and N,N-dimethylformamide (DMF).
[0034] The benzyl halide used for the benzyl protection is preferably benzyl chloride or benzyl bromide.
[0035] The benzyl protection is carried out under basic conditions.
[0036] The alkaline compound providing the alkaline condition is preferably one or more of potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo(5,4,0)-7-undecene (DBU).
[0037] The molar ratio of the compound 4, the benzyl halide and the base is preferably 1:(1-1.1):(1.1-1.5).
[0038] The reaction temperature is preferably 20-80° C., and the reaction time is preferably 1-10 h.
[0039] In the step (4), the reaction solvent is preferably one or more of tetrahydrofuran, toluene, acetonitrile, and N,N-dimethylformamide (DMF).
[0040] The reaction is carried out under alkaline conditions.
[0041] The alkaline compound providing the alkaline condition is preferably one or more of sodium hydride, lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), and potassium bis(trimethylsilyl)amide (KHMDS).
[0042] The carbonate is preferably dimethyl carbonate or diethyl carbonate.
[0043] The molar ratio of the compound 5, the carbonate and the basic compound is preferably 1:(1-3):(1-3).
[0044] The reaction temperature is preferably 20-80° C., and the reaction time is preferably 1-10 h.
[0045] In the step (5), the solvent for the bromination reaction is preferably one or more of dichloromethane, chloroform, ethyl acetate, acetonitrile and tetrahydrofuran.
[0046] The bromination reagent of the bromination reaction is preferably one or more of NBS, bromine, phenyltrimethylammonium bromide, and tetrabutylammonium tribromide.
[0047] The molar ratio of the compound 6 to the brominating agent is preferably 1:(1-1.2).
[0048] The temperature of the bromination reaction is preferably 0-30° C., and the reaction time is preferably 1-5 h.
[0049] There is no particular order in the preparation process of the above-mentioned compound 3 and compound 7. After compound 3 and compound 7 are prepared, they are subjected to a substitution reaction in an organic solvent under the action of a base to prepare compound 8.
[0050] In the step (6), the solvent for the substitution reaction is preferably one or more of tetrahydrofuran, acetone, acetonitrile, toluene, and N,N-dimethylformamide (DMF).
[0051] The substitution reaction is carried out under alkaline conditions.
[0052] The alkaline compound providing the alkaline condition is preferably one or more of potassium carbonate, cesium carbonate, sodium hydride, triethylamine, diisopropylethylamine, and DBU.
[0053] The molar ratio of compound 7 to compound 3 is preferably 1:(1-1.2).
[0054] The temperature of the substitution reaction is preferably 0-30° C., and the reaction time is preferably 1-5 h.
[0055] Then, compound 8 is reduced with a reducing agent in an organic solvent to prepare compound 9.
[0056] In step (7), the solvent for the reduction reaction is preferably one or more of tetrahydrofuran, methanol and ethanol.
[0057] The reducing agent for the reduction reaction is preferably one or more of lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride (DIBAL-H).
[0058] The molar ratio of the compound 8 to the reducing agent is preferably 1:(3-3.5).
[0059] The temperature of the reduction reaction is preferably 0-80° C., and the reaction time is preferably 1-16 h.
[0060] Finally, compound 9 is debenzylated in an organic solvent to prepare (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol.
[0061] In step (8), the solvent for debenzylation is preferably one or more of methanol, ethanol, ethyl acetate and dichloromethane.
[0062] The catalyst for debenzylation protection is preferably one or more of palladium carbon, palladium hydroxide carbon, and Raney nickel.
[0063] The molar ratio of the compound 9 to the catalyst is preferably 1:(0.05-0.1).
[0064] The reaction temperature of the debenzylation protection is preferably 20-30° C., the reaction time is preferably 1-10 h, and the hydrogen pressure is preferably 15-30 psi.
[0065] The (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol prepared by the invention is a racemic body, and chiral separation thereof can be performed to obtain erythro-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol.
[0066] In some specific embodiments of the present invention, the above synthesis method process is as follows:
[0067]
[0068] Compared with the prior art, the present invention provides a method for synthesizing (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol, wherein compound 1, ferulic acid, is used as a starting material, and intermediate 3 is synthesized through esterification and hydrogenation, and compound 3-methoxy-4-hydroxy-acetophenone is used as a starting material, and intermediate 7 is obtained through benzyl protection, claisen condensation reaction, and bromination, and intermediate 7 and intermediate 3 are subjected to nucleophilic substitution, reduction, and hydrogenation debenzylation to obtain the final product. The present invention realizes the artificial synthesis of (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol, which is different from extraction from natural products, has the characteristics of easy raw material availability, simple operation, high yield, etc., and is more suitable for industrial production. DETAILED DESCRIPTION
[0069] In order to better understand the present invention, the present invention is further described below in conjunction with specific embodiments. The technical advantages of the present invention will become clearer with the description, but the embodiments are only exemplary examples and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.
[0070] Example 1 Synthesis of Ethyl Ferulate (Compound 2)
[0071] Add compound 1 ferulic acid (20.0 g, 103.0 mmol) to a three-necked flask, add ethanol (120 mL) and stir to dissolve, then add acetyl chloride (10 mL) dropwise while stirring. Heat and reflux for 6 h, monitor the reaction by TLC until the end. After concentrating under reduced pressure, add ethyl acetate (100 mL) to dissolve, wash with saturated sodium bicarbonate aqueous solution (100 mL), collect the organic phase, and concentrate under reduced pressure to obtain compound 2 as an off-white solid of 20.2 g, with a yield of 88%. HPLC purity is greater than 99%.
[0072] 1 H NMR: (400MHz, CDCl3) δ7.61(d,1H),7.03(d,1H),7.07(dd,1H),6.91(d,1H),6.28(d,1H),5.85(s,1H),4.25(q,2H),3.92(s,3H),1.33(t,3H).
[0073] Example 2 Synthesis of Methyl Ferulate (Compound 2)
[0074] Add compound 1 ferulic acid (20.0 g, 103.0 mmol) to a three-necked flask, add methanol (120 mL), stir to dissolve, and add thionyl chloride (10 mL) dropwise while stirring. Heat and reflux to react for 4 h, and monitor the end point of the reaction by TLC. After concentrating to dryness under reduced pressure, add ethyl acetate (100 mL) to dissolve, wash with saturated sodium bicarbonate aqueous solution (100 mL), collect the organic phase, and concentrate to dryness under reduced pressure to obtain compound 2 as an off-white solid of 18.6 g, with a yield of 87% and a HPLC purity of more than 99%.
[0075] 1 H-NMR: (400MHz, CDCl3) δ7.58(d,1H),6.96(dd,1H),6.96(d,1H),6.96(d,1H),6.86(d,1H),6.25(d,1H),6.14(bs,1H),3.83(s,3H),3.75(s,3H)
[0076] Example 3 Synthesis of ethyl 3-(3-hydroxy-4-methoxyphenyl)propionate (Compound 3)
[0077] Ethyl ferulate (20.0 g, 90.0 mmol) was added to a three-necked flask, methanol (200 mL) was added to dissolve, palladium carbon (1 g, 10%) was added under stirring, nitrogen was replaced 3 times, a double-layer hydrogen balloon (15 psi) was used to replace 3 times, the reaction was carried out at room temperature (25°C) for 5 h, and the reaction end point was monitored by TLC. The reaction solution was filtered under reduced pressure, the filtrate was collected, and it was concentrated to dryness under reduced pressure to obtain compound 3 as a gray slowly crystallizing solid of 19.8 g, with a yield of 98% and a HPLC purity of more than 99%.
[0078] Example 4 Synthesis of methyl 3-(3-hydroxy-4-methoxyphenyl)propionate (Compound 3)
[0079] Methyl ferulate (20.0 g, 71.3 mmol) was added to a three-necked flask, methanol (200 mL) was added to dissolve, palladium carbon (1 g, 10%) was added under stirring, nitrogen was replaced 3 times, a double-layer hydrogen balloon (15 psi) was used to replace 3 times, the reaction was carried out at room temperature (25°C) for 5 h, and the reaction end point was monitored by TLC. The reaction solution was filtered under reduced pressure, the filtrate was collected, and it was concentrated to dryness under reduced pressure to obtain compound 3 as a gray slowly crystallizing solid of 19.6 g, with a yield of 97% and a HPLC purity of more than 99%.
[0080] Example 5 Synthesis of 1-(3-methoxy-4-benzyloxyphenyl)ethanone (Compound 5)
[0081] Compound 4 (20.0 g, 120.4 mmol, 1.00 eq) was added to a three-necked flask, DMF (100 mL) was added, and the mixture was stirred to dissolve, and benzyl chloride (16.0 g, 126.4 mmol, 1.05 eq) and potassium carbonate (20.0 g, 144.4 mmol, 1.20 eq) were added, and the temperature was raised to 80°C for 3 h. The reaction end point was monitored by TLC. The reaction was cooled to room temperature, and the reaction solution was added to water (200 mL). A large amount of white solid was precipitated, and the solid was filtered and collected. The solid was rinsed with n-heptane (100 mL) and dried to obtain 1-(3-methoxy-4-benzyloxyphenyl)ethanone (compound 5) as a white solid of 28.4 g, with a yield of 92% and a HPLC purity of more than 99%.
[0082] Example 6 Synthesis of 1-(3-methoxy-4-benzyloxyphenyl)ethanone (Compound 5)
[0083] Compound 4 (20.0 g, 120.4 mmol, 1.00 eq) was added to a three-necked flask, DMF (100 mL) was added, and the mixture was stirred to dissolve, and benzyl bromide (21.6 g, 126.4 mmol, 1.05 eq) and potassium carbonate (20.0 g, 144.4 mmol, 1.20 eq) were added, and the temperature was raised to 80°C for reaction for 3 h, and the reaction end point was monitored by TLC. The reaction was cooled to room temperature, and the reaction solution was added to water (200 mL), and a large amount of white solid was precipitated. The solid was filtered and collected, and the solid was rinsed with n-heptane (100 mL) and dried to obtain 1-(3-methoxy-4-benzyloxyphenyl)ethanone (compound 5) as a white solid of 28.2 g, with a yield of 92% and a HPLC purity of more than 99%.
[0084] Example 7 Synthesis of ethyl 2-(3-methoxy-4-benzyloxybenzoyl)acetate (Compound 6)
[0085] Add 200mL dry THF, diethyl carbonate (27.7g, 234.1mmol, 3.00eq) and NaH (9.4g, 234.1mmol, 3.00eq, 60%) to a three-necked flask; dissolve compound 5 (20.0g, 78.0mmol, 1.00eq) in 200mL dry THF, add dropwise to the reaction under stirring at room temperature (25±5°C), heat to 66°C, reflux and stir for 10h, and monitor the reaction to the end point by TLC. Add the reaction dropwise to 800mL water, adjust the pH to neutral with glacial acetic acid, extract with dichloromethane, collect the organic phase, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a dark brown solid crude product. The crude product was added to MTBE (80 mL) and ethyl acetate (5 mL), stirred at room temperature for 0.5 h, and filtered to obtain ethyl 2-(3-methoxy-4-benzyloxybenzoyl)acetate (Compound 6) as a yellow solid (19.1 g). The yield was 74.6% and the HPLC purity was greater than 95%.
[0086] 1 H-NMR: (400MHz, CDCl3) δ7.54(d,J=2.0Hz,1H),7.47–7.30(m,6H),6.91(d,1H),5.22(s,2H),4.20(q,2H),3.94(d,5H),1.25(t,3H).
[0087] Example 8 Synthesis of methyl 2-(3-methoxy-4-benzyloxybenzoyl)acetate (Compound 6)
[0088] Add 200mL dry THF, dimethyl carbonate (17.2g, 190.8mmol, 3.00eq) and NaH (7.6g, 190.8mmol, 3.00eq, 60%) to a three-necked flask; dissolve compound 5 (20.0g, 63.6mmol, 1.00eq) in 200mL dry THF, add dropwise to the reaction under stirring at room temperature (25±5°C), heat to 66°C, reflux and stir for 10h, and monitor the reaction to the end point by TLC. Add the reaction dropwise to 800mL water, adjust the pH to neutral with glacial acetic acid, extract with dichloromethane, collect the organic phase, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a dark brown solid crude product. The crude product was added to MTBE (80 mL) and ethyl acetate (5 mL), stirred at room temperature for 0.5 h, and filtered to obtain methyl 2-(3-methoxy-4-benzyloxybenzoyl)acetate (Compound 6) as a yellow solid (16.4 g), with a yield of 71.1% and a HPLC purity of more than 95%
[0089] 1H-NMR: (400MHz, CDCl3) δ7.54(d,J=2.0Hz,1H),7.47–7.31(m,6H),6.90(d,1H),5.22(s,2H),3.92(s,2H),3.91(s,3H),3.71(s,3H).
[0090] Example 9 Synthesis of ethyl 2-(3-methoxy-4-benzyloxybenzoyl)-2-bromoacetate (Compound 7)
[0091] Compound 6 (15.0 g, 45.7 mmol, 1.00 eq) was added to a three-necked flask, and 150 ml of chloroform was added. The mixture was stirred to dissolve. Bromine (8.9 g, 45.7 mmol, 1.00 eq) was added dropwise at 0-5 °C for 15 min. The reaction end point was monitored by TLC. Saturated aqueous sodium sulfite solution (100 mL) was added to the reaction, and the mixture was stirred at room temperature (25 °C) for 0.5 h. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phase was collected, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain ethyl 2-(3-methoxy-4-benzyloxybenzoyl)-2-bromoacetate (Compound 7), 17.9 g of yellow solid, with a yield of 96% and a HPLC purity of more than 99%.
[0092] Example 10 Synthesis of methyl 2-(3-methoxy-4-benzyloxybenzoyl)-2-bromoacetate (Compound 7)
[0093] Compound 6 (15.0 g, 47.7 mmol, 1.00 eq) was added to a three-necked flask, and 150 ml of chloroform was added. The mixture was stirred to dissolve. NBS (8.5 g, 47.7 mmol, 1.00 eq) chloroform solution was added dropwise at 0-5 ° C. The addition was completed in 15 min, and the reaction end point was monitored by TLC. Water (100 mL) was added to the reaction, and the mixture was stirred at room temperature (25 ° C) for 0.5 h. The aqueous phase was extracted with ethyl acetate (50 mL × 2), and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 2-(3-methoxy-4-benzyloxybenzoyl)-2-bromoacetic acid methyl ester (Compound 7) as a yellow solid of 15.4 g, with a yield of 82.6% and a HPLC purity of more than 96%.
[0094] Example 11 Synthesis of ethyl 2-(3-methoxy-4-benzyloxybenzoyl)-2-(4-(3'-propionic acid ethyl)-2-methoxyphenoxy)acetate (Compound 8)
[0095] To a three-necked flask, ethyl 3-(3-hydroxy-4-methoxyphenyl)propanoate (compound 3) (10.0 g, 45.0 mmol, 1.00 eq), DMF (100 ml), and potassium carbonate (7.5 g, 54 mmol, 1.20 eq) were added, and the mixture was stirred at room temperature for 1 h. To the reaction mixture, ethyl 2-(3-benzyloxy-4-methoxybenzoyl)-2-bromoacetate (compound 7) (17.4 g, 42.8 mmol, 0.95 eq) was added, and the mixture was stirred at room temperature for 3 h. The reaction endpoint was monitored by TLC. The reaction solution was poured into 500 mL of water and extracted with ethyl acetate (100 mL x 2). The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain ethyl 2-(3-methoxy-4-benzyloxybenzoyl)-2-(4-(3'-ethyl propionate)-2-methoxyphenoxy)acetate (Compound 8) as a yellow-brown solid (21.4 g). The yield was 86% and the HPLC purity was greater than 99%.
[0096] Example 12 Synthesis of methyl 2-(3-methoxy-4-benzyloxybenzoyl)-2-(4-(3'-methyl propionate)-2-methoxyphenoxy)acetate (Compound 8)
[0097] To a three-necked flask, 3-(3-hydroxy-4-methoxyphenyl)propionic acid methyl ester (compound 3) (10.0 g, 45.0 mmol, 1.00 eq), DMF (100 ml), potassium carbonate (7.5 g, 54 mmol, 1.20 eq) were added, and the mixture was stirred at room temperature for 1 h. To the reaction mixture, 2-(3-benzyloxy-4-methoxybenzoyl)-2-bromoacetic acid methyl ester (compound 7) (16.8 g, 42.8 mmol, 0.95 eq) was added, and the mixture was stirred at room temperature for 3 h. The reaction endpoint was monitored by TLC. The reaction solution was poured into 500 mL of water and extracted with ethyl acetate (100 mL x 2). The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain methyl 2-(3-methoxy-4-benzyloxybenzoyl)-2-(4-(3'-methyl propionate)-2-methoxyphenoxy)acetate (Compound 8) as a yellow-brown solid (20.2 g). The yield was 86.0% and the HPLC purity was greater than 99%.
[0098] Example 13 Synthesis of 1-(3-methoxy-4-benzyloxyphenyl)-2-(4-(3'-hydroxypropyl)-2-methoxyphenoxy)-1,3-propanediol (Compound 9)
[0099] Add 2-(3-methoxy-4-benzyloxybenzoyl)-2-(4-(3'-ethyl propionate)-2-methoxyphenoxy)ethyl acetate (Compound 8) (20.0 g, 36.3 mmol, 1.00 eq) and 400 mL of anhydrous THF to a three-necked flask, add LAH (4.6 g, 119.8 mmol, 3.30 eq) at 0-5°C, react at room temperature (25°C) for 16 h, and monitor the reaction end point by TLC. Add sodium sulfate decahydrate (20 g) at 0-5°C in an ice bath, stir for 0.5 h, filter, collect the filtrate, and concentrate under reduced pressure to obtain 1-(3-methoxy-4-benzyloxyphenyl)-2-(4-(3'-hydroxypropyl)-2-methoxyphenoxy)-1,3-propanediol (Compound 9) as a yellow crystalline solid of 11.8 g, with a yield of 69.4% and a HPLC purity of more than 99%.
[0100] 1 H-NMR: (400MHz, CDCl3) δ7.80(d,1H),7.70(s,1H),7.39(m,5H),6.89(dd,2H),6.73(s,1H),6.65(d,1H),5.69(s ,1H),5.23(s,2H),4.52(q,2H),4.11(q,2H),3.93(s,3H),3.77(s,3H),2.87(t,2H),2.57(t,2H),1.22(td,6H).
[0101] Example 14 Synthesis of 1-(3-methoxy-4-benzyloxyphenyl)-2-(4-(3'-hydroxypropyl)-2-methoxyphenoxy)-1,3-propanediol (Compound 9)
[0102] Add 2-(3-methoxy-4-benzyloxybenzoyl)-2-(4-(3'-methyl propionate)-2-methoxyphenoxy)acetic acid methyl ester (Compound 8) (20.0 g, 38.3 mmol, 1.00 eq) and 400 mL of anhydrous THF to a three-necked flask, add LAH (4.8 g, 126.4 mmol, 3.30 eq) at 0-5°C, react at room temperature (25°C) for 16 h, and monitor the reaction end point by TLC. Add sodium sulfate decahydrate (20 g) at 0-5°C in an ice bath, stir for 0.5 h, filter, collect the filtrate, and concentrate under reduced pressure to obtain 1-(3-methoxy-4-benzyloxyphenyl)-2-(4-(3'-hydroxypropyl)-2-methoxyphenoxy)-1,3-propanediol (Compound 9) as a yellow crystalline solid of 12.0 g, with a yield of 67.0% and a HPLC purity of more than 99%.
[0103] Example 15 Synthesis of (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol
[0104] 1-(3-methoxy-4-benzyloxyphenyl)-2-(4-(3'-hydroxypropyl)-2-methoxyphenoxy)-1,3-propanediol (Compound 9) (10.0 g, 21.3 mmol) was added to a three-necked flask, methanol (100 mL) was added to dissolve, palladium carbon (0.5 g, 10%) was added under stirring, nitrogen was replaced 3 times, and a double-layer hydrogen balloon (15 psi) was used to replace 3 times, and the reaction was carried out at room temperature (25°C) for 5 hours, and the reaction end point was monitored by TLC. The reaction solution was filtered under reduced pressure, the filtrate was collected, and it was concentrated under reduced pressure to obtain (±)-guaiacylglycerol-β-O-4'-dihydroconiferyl alcohol, 7.1 g of white solid, with a yield of 88%, and a HPLC purity of more than 99%.
[0105] 1 H-NMR: (400MHz, CD3OD) δ7.03(d,1H),6.84(m,2H),6.80(d,1H),6.76(d,1H),6.67(dd,1H),4. 85(d,1H),4.31(td,1H),3.87(dd,3H),3.80(d,7H),3.56(t,2H),2.61(dd,2H),1.81(dq,2H).
[0106] 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 synthesizing (±)-guaiacylglycerol-β-O-4'-dihydroconiferyl alcohol, comprising the following steps: (1) subjecting ferulic acid to an esterification reaction with an alcohol compound in the presence of a catalyst to prepare compound 2; (2) subjecting compound 2 to a catalytic hydrogenation reduction reaction to prepare compound 3; (3) benzyl protecting compound 4 to prepare compound 5; (4) reacting compound 5 with carbonate to prepare compound 6; (5) treating compound 6 with a brominating agent to carry out a bromination reaction to prepare compound 7; (6) Compound 3 and Compound 7 are mixed to carry out a substitution reaction to prepare Compound 8; (7) subjecting compound 8 to a reduction reaction to prepare compound 9; (8) Debenzylation of compound 9 to prepare (±)-guaiacylglycerol-β-O-4′-dihydroconiferyl alcohol; 2. The synthesis method according to claim 1, characterized in that In the step (1), the alcohol compound is selected from C1 to C6 monohydric alcohols; The catalyst is selected from one or more of sulfuric acid, hydrogen chloride, thionyl chloride, acetyl chloride, and oxalyl chloride; The mass volume ratio of the ferulic acid, the alcohol compound and the catalyst is 1 g: (1-10) mL: (0.5-2) mL; The temperature of the esterification reaction is 0-80°C and the time is 1-10h.
3. The synthesis method according to claim 1, characterized in that In the step (2), the solvent for the catalytic hydrogenation reduction reaction is selected from one or more of methanol, ethanol, ethyl acetate, and dichloromethane; The catalyst for the catalytic hydrogenation reduction reaction is selected from one or more of palladium carbon, palladium hydroxide carbon, and Raney nickel; The molar ratio of the compound 2 to the catalyst is 1:(0.05-0.1); The temperature of the catalytic hydrogenation reduction reaction is 20-30° C., the reaction time is 1-10 h, and the hydrogen pressure is 15-30 psi.
4. The synthesis method according to claim 1, characterized in that In the step (3), the reaction solvent for benzyl protection is selected from one or more of dichloromethane, tetrahydrofuran, acetone, acetonitrile, 1,2-dichloroethane, 1,4-dioxane, and N,N-dimethylformamide; The benzyl halide used in the benzyl protection is benzyl chloride or benzyl bromide; The benzyl protection is carried out under alkaline conditions; The alkaline compound providing the alkaline condition is selected from one or more of potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, and DBU; The molar ratio of the compound 4, benzyl halide and base is 1:(1-1.1):(1.1-1.5); The reaction temperature is 20-80°C and the reaction time is 1-10h.
5. The synthesis method according to claim 1, characterized in that In the step (4), the reaction solvent is selected from one or more of tetrahydrofuran, toluene, acetonitrile, and N,N-dimethylformamide; The reaction is carried out under alkaline conditions; The alkaline compound providing the alkaline condition is selected from one or more of sodium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide; The carbonate is selected from dimethyl carbonate or diethyl carbonate; The molar ratio of the compound 5, the carbonate ester and the basic compound is 1:(1-3):(1-3); The reaction temperature is 20-80°C and the reaction time is 1-10h.
6. The synthesis method according to claim 1, characterized in that In the step (5), the solvent for the bromination reaction is selected from one or more of dichloromethane, chloroform, ethyl acetate, acetonitrile and tetrahydrofuran; The bromination reagent of the bromination reaction is selected from one or more of NBS, bromine, phenyltrimethylammonium bromide, and tetrabutylammonium tribromide; The molar ratio of the compound 6 to the bromination reagent is 1:(1-1.2); The temperature of the bromination reaction is 0-30°C, and the reaction time is 1-5h.
7. The synthesis method according to claim 1, characterized in that In the step (6), the solvent for the substitution reaction is selected from one or more of tetrahydrofuran, acetone, acetonitrile, toluene, and N,N-dimethylformamide; The substitution reaction is carried out under alkaline conditions; The alkaline compound providing the alkaline condition is selected from one or more of potassium carbonate, cesium carbonate, sodium hydride, triethylamine, diisopropylethylamine, and DBU; The molar ratio of compound 7 to compound 3 is 1:(1-1.2); The temperature of the substitution reaction is 0-30°C, and the reaction time is 1-5h.
8. The synthesis method according to claim 1, characterized in that In step (7), the solvent for the reduction reaction is selected from one or more of tetrahydrofuran, methanol, and ethanol; The reducing agent of the reduction reaction is selected from one or more of lithium aluminum hydride, sodium borohydride, and DIBAL-H; The molar ratio of the compound 8 to the reducing agent is 1:(3-3.5); The temperature of the reduction reaction is 0-80°C, and the reaction time is 1-16h.
9. The synthesis method according to claim 1, characterized in that In the step (8), the solvent for debenzylation is selected from one or more of methanol, ethanol, ethyl acetate and dichloromethane; The catalyst for debenzylation protection is one or more of palladium carbon, palladium hydroxide carbon, and Raney nickel; The molar ratio of the compound 9 to the catalyst is 1:(0.05-0.1); The reaction temperature of the debenzylation protection is 20-30° C., the reaction time is 1-10 h, and the hydrogen pressure is 15-30 psi.