A method for preparing dehydrodiconiferyl alcohol diglucoside

Abstract

The present invention relates to a preparation method of bismagnolin, belonging to the field of chemical synthesis of natural organic drugs. Starting from compounds 1 and 4, the present invention successfully constructs a dibenzofuran ring to obtain monomers, and finally completes the chemical synthesis of the natural product bismagnolin through oxidative coupling. This idea and synthetic route are innovative. Among them, compound 1 is synthesized from inexpensive p-allylanisole, and compound 4 is obtained from 1,2,4-trimethoxybenzene to obtain the functionalized compound 4. These methods are all conventional reactions in the laboratory, with a concise route, low operation difficulty, and good yield. The present invention develops a synthetic strategy for bismagnolin. This idea and synthetic route are innovative and lay a certain foundation for the subsequent chemical synthesis of bismagnolin.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis of natural organic drugs, and particularly relates to a preparation method of bismagnolin. Background Art

[0002] Bismagnolin is a lignan natural product extracted from Magnolia officinalis of Magnoliaceae. It has a dibenzofuran skeleton and is symmetric, and can be regarded as dimerized from two identical monomers. Relevant experiments show that bismagnolin has strong inhibitory activity against tumor cells from various tissue sources, and its IC 50 is between 0.4 μM - 0.75 μM, while its inhibitory ability against normal cells is weak. Bismagnolin can also inhibit the colony formation ability of tumor cells, significantly promote apoptosis of tumor cells, and has low toxicity and side effects. Anti-tumor drugs can be prepared using bismagnolin or its pharmaceutically acceptable salts and derivatives of bismagnolin, and the application prospect is very broad.

[0003] There are many aromatic natural products in nature, especially natural products with a dibenzofuran ring similar to bismagnolin and natural products formed by oxidative coupling of aromatics. The existing methods for constructing the dibenzofuran ring mainly include intramolecular carbon-carbon bond coupling under palladium catalysis, intermolecular construction of the dibenzofuran ring, and intramolecular dehydration to construct an oxygen-bridged ring under the action of an acid. For the oxidative coupling of aromatic natural products, a variety of metal-catalyzed oxidative coupling reactions have been developed, including vanadium, iron, copper, rhodium, etc. However, due to the conjugated structure of the aromatic ring and the electronic effect of the attached groups, it often has multiple reaction sites. Therefore, the metal-catalyzed oxidative coupling reaction of the aromatic ring has poor generality, and there are problems such as low reaction yield and product impurity. And currently, most of the construction methods of the benzofuran ring only construct a simple dibenzofuran structure, and there are great challenges in the construction of polysubstituted dibenzofurans. The reason is that the two benzene rings of dibenzofuran are connected by carbon-carbon bonds and carbon-oxygen-carbon bonds. When there are many substituents on both benzene rings, it will affect the construction of carbon-carbon bonds and carbon-oxygen-carbon bonds, and there are many difficulties such as the selection of raw materials, the connection order of the two bonds, and the influence of substituents on the reaction.

[0004] Currently, there is no relevant report on the chemical preparation method of bismagnolin. Therefore, exploring a concise and efficient chemical synthesis strategy for bismagnolin is of great significance for the drug application of bismagnolin. Summary of the Invention

[0005] The purpose of the present invention is to overcome the problems existing in the above-mentioned prior art, and provide a preparation method of bismagnolin with a concise route, low operation difficulty, and good yield.

[0006] The present invention is implemented through the following technical solutions:

[0007] The present invention provides a method for preparing magnolignan, comprising the following steps:

[0008] (1) Compounds 1 and 4 are added to a mixed solution of an organic solvent and water, and refluxed at 95°C to 105°C for 8 h to 12 h under the action of a palladium catalyst and a carbonate to obtain Compound 5; the reaction formula is as follows:

[0009]

[0010] (2) The obtained Compound 5 is dissolved in an organic solvent, and boron tribromide is added at a temperature of -85°C to -70°C, and the temperature is raised to 15°C to 30°C for reaction for 2 h to 6 h to obtain Compound 6; the reaction formula is as follows:

[0011]

[0012] (3) Hydroquinone, the obtained Compound 6 and sulfuric acid are added to acetic acid, refluxed at 110°C to 120°C for 15 min to 25 min, and cooled to obtain Compound 7; the reaction formula is as follows:

[0013]

[0014] (4) The obtained Compound 7 is subjected to an oxidative coupling reaction under the action of a peroxide and a ferric salt to obtain the magnolignan; the reaction formula is as follows:

[0015]

[0016] The present invention uses Compounds 1 and 4 as starting materials, successfully constructs a dibenzofuran ring to obtain monomers, and then performs oxidative coupling of the monomers to obtain magnolignan. The preparation method of the present invention is a conventional reaction in the laboratory, with a simple route, low operation difficulty, good yield, and develops a synthetic strategy for magnolignan, laying a certain foundation for the subsequent chemical synthesis of magnolignan.

[0017] As a preferred embodiment of the method for preparing magnolignan according to the present invention, the step (1) satisfies at least one of the following:

[0018] (1-1) The molar ratio of Compound 4, Compound 1, the palladium catalyst, and the carbonate is 1:(1 to 1.3):(0.01 to 0.1):(3 to 5);

[0019] (1-2) The concentration of Compound 4 in the reaction solution is 0.15 mmol / mL to 0.3 mmol / mL;

[0020] (1-3) The base is a carbonate;

[0021] The palladium catalyst described in (1-4) is tetrakis(triphenylphosphine)palladium;

[0022] In the mixed solution described in (1-5), the volume ratio of the organic solvent to water is (2.9 - 6):1;

[0023] The organic solvent described in (1-6) is 1,4-dioxane, acetonitrile, or a mixed solution of toluene and methanol.

[0024] Preferably, the reaction for preparing Compound 5 in step (1) is quenched with a saturated ammonium chloride solution.

[0025] As a preferred embodiment of the method for preparing the bismagnolignan of the present invention, step (2) satisfies at least one of the following:

[0026] (2-1) The concentration of Compound 5 in the reaction solution is 0.1 mmol / mL - 0.3 mmol / mL;

[0027] (2-2) The organic solvent is dichloromethane, benzene, or carbon tetrachloride;

[0028] (2-3) The molar ratio of Compound 5 to boron tribromide is 1:(4 - 5).

[0029] Preferably, the reaction for preparing Compound 6 in step (2) is quenched with ice water.

[0030] As a preferred embodiment of the method for preparing the bismagnolignan of the present invention, step (3) satisfies at least one of the following:

[0031] (3-1) The molar ratio of Compound 6, hydroquinone, and sulfuric acid is 1:(8 - 12):(14 - 18);

[0032] (3-2) The concentration of sulfuric acid is 2 mmol / mL - 4 mmol / mL;

[0033] (3-3) The concentration of Compound 6 in the reaction solution is 0.2 mmol / mL - 0.4 mmol / mL.

[0034] Preferably, the reaction for preparing Compound 7 in step (3) is quenched with a saturated sodium bicarbonate solution.

[0035] As a preferred embodiment of the method for preparing the bismagnolignan of the present invention, step (4) satisfies at least one of the following:

[0036] (4-1) The peroxide is meta-chloroperoxybenzoic acid;

[0037] (4-2) The ferric salt is anhydrous ferric chloride;

[0038] (4-3) The solvent for the oxidative coupling reaction is dichloromethane;

[0039] (4-4) The molar ratio of the compound 7, peroxide and ferric salt is 1:(1-1.3):(0.1-0.3);

[0040] (4-5) The concentration of the compound 7 in the reaction solution is 0.05 mmol / mL - 0.15 mmol / mL;

[0041] (4-6) The temperature of the oxidative coupling reaction is 20°C - 30°C, and the time is 1 h - 2 h.

[0042] Preferably, the reaction for preparing bismagnolignan in step (4) is quenched with water.

[0043] As a preferred embodiment of the method for preparing bismagnolignan according to the present invention, the method for preparing the compound 1 includes the following steps: Dissolve p-allylanisole, tetramethylethylenediamine, and sec-butyllithium in an ether solvent, stir at -85°C to -70°C for ortho-lithiation reaction, then raise the temperature to 15°C to 30°C, add trimethyl borate and stir for 18 h to 24 h, acidify with hydrochloric acid and then stir for 1 h to 2 h to obtain the compound 1; The reaction general formula is as follows:

[0044]

[0045] As a preferred embodiment of the method for preparing bismagnolignan according to the present invention, the method for preparing the compound 1 satisfies at least one of the following:

[0046] (5-1) The ether solvent is tetrahydrofuran;

[0047] (5-2) The molar ratio of p-allylanisole, tetramethylethylenediamine, sec-butyllithium, and trimethyl borate is 1:(1-1.5):(1.5-2.0):(1-1.5);

[0048] (5-3) The concentration of p-allylanisole in the reaction solution is 0.15 mmol / mL - 0.3 mmol / mL.

[0049] Preferably, the concentration of hydrochloric acid for acidification is 1 mol / L, and the acidification is carried out until the pH is 3.

[0050] As a preferred embodiment of the method for preparing bismagnolignan according to the present invention, the method for preparing the compound 4 includes the following steps:

[0051] S1. Dissolve trimethoxybenzene and n-butyllithium in an ether solvent, stir at -85°C to -70°C for ortho-lithiation reaction, then add methyl iodide, and warm up to 15°C to 30°C and stir for 1 h to 2 h to obtain compound 2; 2,3,6-trimethoxytoluene; The reaction formula is as follows:

[0052]

[0053] S2. Add the obtained compound 2, a radical initiator, and N-bromosuccinimide to an organic solvent, and reflux at 80°C to 85°C for 8 h to 12 h under light to obtain compound 3; The reaction formula is as follows:

[0054]

[0055] S3. Dissolve the obtained compound 3, copper(I) iodide, 2,2'-bipyridine, and vinylmagnesium bromide in an organic solvent, and stir at 15°C to 30°C for 6 h to 10 h to obtain compound 4; The reaction formula is as follows:

[0056]

[0057] As a preferred embodiment of the method for preparing the bismagnolin described in the present invention, the step S2 satisfies at least one of the following:

[0058] (6-1) The radical initiator is azobisisobutyronitrile;

[0059] (6-2) The molar ratio of the compound 2, the radical initiator, and N-bromosuccinimide is 1:(0.1 to 0.2):(2.0 to 2.5);

[0060] (6-3) The concentration of the compound 2 in the reaction solution is 0.2 mmol / mL to 0.4 mmol / mL;

[0061] (6-4) The organic solvent is carbon tetrachloride or acetonitrile.

[0062] Preferably, the reaction for preparing compound 3 in step S2 is quenched with water.

[0063] As a preferred embodiment of the method for preparing the bismagnolin described in the present invention, it satisfies at least one of the following:

[0064] (7-1) In the step S1, the ether solvent is tetrahydrofuran;

[0065] (7-2) In the step S1, the molar ratio of trimethoxybenzene, n-butyllithium, and methyl iodide is 1:(1.5 to 2.0):(1 to 1.5);

[0066] In the step S1, the concentration of 1,2,4-trimethoxybenzene in the reaction solution is 0.15 mmol / mL to 0.3 mmol / mL;

[0067] In the step S3, the molar ratio of the compound 3, copper(I) iodide, 2,2'-bipyridine and vinylmagnesium bromide is 1:(0.1 - 0.2):(0.1 - 0.2):(1.5 - 2.0);

[0068] In the step S3, the concentration of the compound 3 in the reaction solution is 0.15 mmol / mL to 0.4 mmol / mL;

[0069] In the step S3, the organic solvent is an ether solvent or dichloromethane.

[0070] Preferably, the reaction for preparing the compound 4 in the step S3 is quenched with a saturated ammonium chloride solution; the reaction for preparing the compound 2 in the step S1 is quenched with a saturated ammonium chloride solution.

[0071] Preferably, all reactions of the present invention are carried out in an inert gas atmosphere.

[0072] Preferably, the preparation method of the present invention further includes extracting, washing, drying, concentrating and purifying the solution after the reaction.

[0073] Preferably, in the step (1), the solution after the reaction is extracted with ethyl acetate for the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain the compound 5.

[0074] Preferably, in the step (2), the solution after the reaction is extracted with dichloromethane for the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain the compound 6.

[0075] Preferably, in the step (3), the solution after the reaction is extracted with dichloromethane for the organic phase, washed with saturated brine and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain the compound 7.

[0076] Preferably, in the step (4), the solution after the reaction is extracted with dichloromethane for the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by ODS column chromatography (200 - 300 mesh silica gel, methanol and water as eluents) to obtain the bismagnolignan.

[0077] Preferably, in the preparation method of Compound 1, after the reaction is completed, the solution is extracted with ethyl acetate to obtain the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel of 200 - 300 mesh, petroleum ether and ethyl acetate as eluents) to obtain Compound 1.

[0078] Preferably, in Step S1, after the reaction is completed, the solution is extracted with ethyl acetate to obtain the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel of 200 - 300 mesh, petroleum ether and ethyl acetate as eluents) to obtain Compound 2.

[0079] Preferably, in Step S2, after the reaction is completed, the solution is extracted with dichloromethane to obtain the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain Compound 3.

[0080] Preferably, in Step S3, after the reaction is completed, the solution is extracted with methyl tert - butyl ether to obtain the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel of 200 - 300 mesh, petroleum ether and ethyl acetate as eluents) to obtain Compound 4.

[0081] The present invention has the following beneficial effects: Bimagnolin has a strong inhibitory ability against tumor cells. The present invention has created an efficient and feasible route. Starting from Compound 1 and Compound 4 with as little use of expensive transition metals as possible, the dibenzofuran ring was successfully constructed to obtain the monomer, and finally the chemical synthesis of the natural product bimagnolin was completed through oxidative coupling. This idea and synthetic route are innovative. Among them, Compound 1 was synthesized from inexpensive p - allylanisole as the raw material, and Compound 4 was obtained from 1,2,4 - trimethoxybenzene to obtain the functionalized Compound 4. This method does not have overly harsh conditions, all are conventional reactions in the laboratory, the route is concise, the operation difficulty is low, and the yields of most reactions are good. The present invention has developed a synthetic strategy for bimagnolin, laying a foundation for the synthesis of bimagnolin and accelerating its application in anti - tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1 It is the NMR spectrum of the bimagnolin prepared in Example 1;

[0083] Figure 2 It is the high - resolution NMR spectrum of the bimagnolin prepared in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0084] To better illustrate the purpose, technical solution and advantages of the present invention, the present invention will be further described below with reference to specific examples. Those skilled in the art should understand that the specific examples described herein are only used to explain the present invention and are not used to limit the present invention.

[0085] Unless otherwise specified, the test methods used in the examples are conventional methods; the materials, reagents, etc. used can be obtained from commercial sources unless otherwise specified.

[0086] Example 1

[0087] A method for preparing dihonokiol, comprising the following steps:

[0088] (1) Weigh compound 1 (3.00 g, 15.60 mmol), compound 4 (4.07 g, 14.18 mmol), tetrakis(triphenylphosphine)palladium(0) (0.82 g, 0.71 mmol), and potassium carbonate (42.54 mmol, 5.88 g) into a 250 mL round-bottom flask. Under nitrogen protection, add 47 mL of 1,4-dioxane and 16 mL of water. After refluxing at 100 °C for 10 h, cool to room temperature. After monitoring the reaction to completion by TLC, quench with saturated ammonium chloride solution, extract the organic phase with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 4.24 g of compound 5 with a yield of 84%. Compound 5 is a colorless oil;

[0089] (2) Weigh compound 5 (117.00 mg, 0.33 mmol) into a 25 ml round-bottom flask. Under nitrogen protection, add 3 mL of dichloromethane and cool to -78 °C. Then, dropwise add boron tribromide (1 M in DCM, 1.32 mL, 1.32 mmol). After slowly warming to 25 °C, continue the reaction for 3 h. After monitoring the reaction to completion by TLC, slowly pour into ice water to quench, extract with dichloromethane, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 87 mg of compound 6 with a yield of 89%. Compound 6 is a red oil;

[0090] (3) Weigh hydroquinone (4.33 g, 39.32 mmol) and sulfuric acid (2 M, 31.5 mL) into a 100 mL round-bottom flask, add acetic acid (15 mL) and reflux at 115 °C. Weigh compound 6 (1.17 g, 3.93 mmol) and dissolve it in a small amount of acetic acid, and then dropwise add it to the above reflux solution. Continue refluxing for 15 min and then stop heating. After the system cools, after monitoring the reaction to completion by TLC, slowly add saturated sodium bicarbonate solution to quench, extract with dichloromethane, wash the organic phase twice with saturated sodium bicarbonate solution and saturated brine respectively, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 605 mg of compound 7 with a yield of 55%. Compound 7 is a white solid;

[0091] (4) Weigh compound 7 (497 mg, 1.71 mmol) into a 100 ml round-bottom flask. Under nitrogen protection, add 20 mL of dichloromethane and stir to dissolve. Then weigh anhydrous ferric chloride (28 mg, 0.17 mmol) and m-chloroperoxybenzoic acid (300 mg, 1.71 mmol) and add them. Stir at 25 °C for 1 h. After monitoring the reaction by TLC until it is completed, quench it with water, extract with dichloromethane. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and then concentrate in vacuo. The residue is purified by ODS column chromatography (using methanol and water as eluents) to obtain 330 mg of bismagnolignan, with a yield of 67%. Bismagnolignan is a white solid.

[0092] The preparation method of compound 1 is as follows: Add p-allylanisole (5.0 g, 33.74 mmol) to a 100 mL dry round-bottom flask. Under a nitrogen atmosphere, add 120 mL of tetrahydrofuran and stir to dissolve. Slowly dropwise add tetramethylethylenediamine (5.06 mL, 33.74 mmol) and sec-butyllithium (39.00 mL, 50.61 mmol of a 1.3 M solution in hexanes) at -78 °C. The dropping time of sec-butyllithium is more than 10 minutes. Stir for 1 h, then let the reaction naturally rise to 25 °C and stir for 1 h. Then dropwise add trimethyl borate (3.77 mL, 33.74 mmol) and stir for another 24 h. Acidify the reaction with 1 M hydrochloric acid to a pH of 3, and then stir for 1 h. After the reaction is completed, dilute with ethyl acetate and extract the organic phase. Wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. After purification by column chromatography (using silica gel of 200 - 300 mesh, petroleum ether and ethyl acetate as eluents), 4.08 g of compound 1 is obtained, with a yield of 63%. Compound 1 is a colorless solid.

[0093] The preparation method of Compound 4 is as follows: S1. Add 1,2,4-trimethoxybenzene (10 g, 59.45 mmol) into a 100 mL dry round-bottom flask, add 120 mL of tetrahydrofuran and stir to dissolve under a nitrogen atmosphere. Dropwise add n-butyllithium (36.00 mL of 2.5 M solution in hexane, 89.18 mmol) at -78 °C, and the dropping time is more than 5 minutes. After the system reacts for 15 min, naturally warm up to 25 °C, continue to stir for 1 h, then cool the reaction to -78 °C again, add methyl iodide (5.60 mL, 59.45 mmol), and slowly warm up to 25 °C, continue to stir for 1 h. After TLC detects that the reaction is complete, quench the reaction with 200 mL of saturated ammonium chloride solution, extract the mixed system with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase with anhydrous sodium sulfate and concentrate it by distillation under reduced pressure. Purify it by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 10.72 g of Compound 2 with a yield of 99%. Compound 2 is a colorless solid;

[0094] S2. Add Compound 2 (0.95 g, 5.22 mmol) and azobisisobutyronitrile (0.09 g, 0.52 mmol) into a 100 mL dry round-bottom flask, dissolve it with 20 mL of carbon tetrachloride under nitrogen protection, and then add N-bromosuccinimide (2.14 g, 11.48 mmol). Reflux at 80 °C under light for 8 h. After TLC monitors that the reaction is complete, cool to room temperature, quench with water, extract the organic phase with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate and concentrate in vacuo to obtain 1.62 g of Compound 3 with a yield of 91%. Compound 3 is a white solid;

[0095] S3. Add Compound 3 (5.67 g, 16.66 mmol), copper(I) iodide (0.26 g, 1.67 mmol) and 2,2'-bipyridine (0.32 mg, 1.67 mmol) into a 200 mL dry round-bottom flask, add 40 mL of tetrahydrofuran under nitrogen protection and stir well. Cool to -20 °C, dropwise add vinylmagnesium bromide (25 mL of a 1.0 M solution in THF, 25 mmol), and then slowly warm up the reaction system to 25 °C and stir for 8 h. After TLC monitors that the reaction is complete, quench with saturated ammonium chloride solution, extract the organic phase with methyl tert-butyl ether, wash with saturated brine, dry with anhydrous sodium sulfate and concentrate in vacuo. Purify it by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 3.95 g of Compound 4 with a yield of 83%. Compound 4 is a colorless oil.

[0096] The nuclear magnetic spectrum and high-resolution data of the obtained bismagnolignan are as Figure 1 and Figure 2As shown, where the nuclear magnetic data are as follows: 1 H NMR(500MHz,Chloroform-d)δ:7.39(d,J=8.4Hz,2H),7.03(d,J=8.4Hz,2H),6.55(s,2H),6.24(ddt,J=16.5,10.2,6.2Hz,2H),5.99(s,2H),5.55(ddt,J=16.8,10.1,6.6Hz,2H),5.28(dd,J=17.1,2.0Hz,2H),5.19(dd,J=10.0,1.8Hz,2H),4.83(dd,J=10.0,1.9Hz,2H),4.74(dd,J=17.0,1.9Hz,2H),3.89(d,J=6.2Hz,4H),3.11(d,J=6.8Hz,4H). 13 C NMR(126MHz,Chloroform-d)δ:155.0,150.4,143.2,137.5,137.2,135.1,134.0,126.5,124.1,120.5,116.0,115.5,114.2,111.1,110.7,110.3,39.6,28.5.

[0097] The high-resolution data are as follows: HRMS calcd for C 36 H 30 O 6 Na[M+Na] + :581.1940,found 581.1934. Example 2

[0098] A method for preparing bismagnolignan, comprising the following steps:

[0099] (1) Weigh compound 4 (4.07 g, 14.18 mmol, 1 equivalent), compound 1 (1.3 equivalents), tetrakis(triphenylphosphine)palladium(0) (0.1 equivalent), and potassium carbonate (5 equivalents) into a 250 mL round-bottom flask. Under nitrogen protection, add 47 mL of 1,4-dioxane and 16 mL of water. After refluxing at 105 °C for 12 h, cool to room temperature. After monitoring the reaction to completion by TLC, quench with saturated ammonium chloride solution, extract the organic phase with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 4.03 g of compound 5 with a yield of 82%. Compound 5 is a colorless oil;

[0100] (2) Weigh 5 (117.00 mg, 0.33 mmol, 1 equiv) into a 25 mL round-bottom flask. Under nitrogen protection, add 1.1 mL of dichloromethane and cool to -85 °C. Then, dropwise add boron tribromide (5 equiv). Slowly warm up to 30 °C and continue the reaction for 6 h. After monitoring the completion of the reaction by TLC, slowly pour it into ice water to quench. Extract with dichloromethane, wash with saturated brine. The organic phase is dried over anhydrous sodium sulfate and concentrated in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 79 mg of 6, with a yield of 81%. Compound 6 is a red oil;

[0101] (3) Weigh hydroquinone (8 equiv) and sulfuric acid (14 equiv) into a 100 mL round-bottom flask, add acetic acid and reflux at 120 °C. Weigh 6 (1.17 g, 3.93 mmol, 1 equiv) and dissolve it in a small amount of acetic acid, and dropwise add it to the above reflux solution. The concentration of 6 in the solution system is 0.4 mmol / mL. Continue refluxing for 25 min, then stop heating. After the system cools down, monitor the completion of the reaction by TLC, and slowly add saturated sodium bicarbonate solution to quench. Extract with dichloromethane. The organic phase is washed twice with saturated sodium bicarbonate solution and saturated brine respectively, dried over anhydrous sodium sulfate and concentrated in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 590 mg of 7, with a yield of 54%. Compound 7 is a white solid;

[0102] (4) Weigh 7 (497 mg, 1.71 mmol, 1 equiv) into a 100 mL round-bottom flask. Under nitrogen protection, add 20 mL of dichloromethane and stir to dissolve. Weigh anhydrous ferric chloride (0.3 equiv) and m-chloroperoxybenzoic acid (1.3 equiv) and add them. Stir at 30 °C for 2 h. After monitoring the end of the reaction by TLC, quench with water, extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by ODS column chromatography (methanol and water as eluents) to obtain 331 mg of bismagnolignan, with a yield of 67%. Bismagnolignan is a white solid.

[0103] The preparation method of Compound 1 is as follows: Add p-allylanisole (5.0 g, 33.74 mmol, 1 equivalent) into a 100 mL dry round-bottom flask. Under a nitrogen atmosphere, add tetrahydrofuran to make the concentration of p-allylanisole in the system 0.3 mmol / mL. Stir to dissolve. Slowly dropwise add tetramethylethylenediamine (1 equivalent) and sec-butyllithium (1.5 equivalents) at -85 °C. The dropping time of sec-butyllithium is more than 10 minutes. Stir for 1 h, then let the reaction naturally rise to 30 °C and stir for 1 h. Then dropwise add trimethyl borate (1.5 equivalents) and stir for another 24 h. Acidify the reaction with 1 M hydrochloric acid to a pH of 3 and then stir for 2 h. After the reaction is completed, dilute with ethyl acetate and extract the organic phase. Wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under vacuum, and purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 4.12 g of Compound 1 with a yield of 64%. Compound 1 is a colorless solid.

[0104] The preparation method of Compound 4 is as follows: S1. Add 1,2,4-trimethoxybenzene (10 g, 59.45 mmol, 1 equivalent) into a 100 mL dry round-bottom flask. Under a nitrogen atmosphere, add tetrahydrofuran to make the concentration of 1,2,4-trimethoxybenzene in the system 0.3 mmol / mL. Stir to dissolve. Dropwise add n-butyllithium (2 equivalents) at -85 °C. The dropping time is more than 5 minutes. After the system reacts for 15 min, naturally warm up to 30 °C and continue to stir for 1 h. Then cool the reaction to -85 °C again, add methyl iodide (1.5 equivalents), and slowly warm up to 30 °C and continue to stir for 1 h. After TLC detects that the reaction is complete, quench the reaction with 200 mL of saturated ammonium chloride solution. Extract the mixed system with ethyl acetate. Wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 10.33 g of Compound 2 with a yield of 95%. Compound 2 is a colorless solid;

[0105] S2. Add Compound 2 (0.95 g, 5.22 mmol, 1 equivalent) and azobisisobutyronitrile (0.2 equivalent) into a 100 mL dry round-bottom flask. Under nitrogen protection, dissolve with carbon tetrachloride to make the concentration of Compound 2 in the system 0.4 mmol / mL. Then add N-bromosuccinimide (2.5 equivalents). Reflux at 85 °C for 12 h under light. After TLC monitors that the reaction is complete, cool to room temperature, quench with water, extract the organic phase with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate and concentrate under vacuum to obtain 1.63 g of Compound 3 with a yield of 91%. Compound 3 is a white solid;

[0106] S3. In a 200 mL dry round-bottom flask, add compound 3 (5.67 g, 16.66 mmol, 1 equiv), copper(I) iodide (0.2 equiv), and 2,2'-bipyridine (0.2 equiv). Under nitrogen protection, add tetrahydrofuran to make the concentration of compound 3 in the system 0.4 mmol / mL. Stir well, cool to -40 °C, and slowly add vinylmagnesium bromide (2 equiv) dropwise. Then, slowly warm the reaction system to 30 °C and stir for 10 h. After monitoring the reaction to completion by TLC, quench with saturated ammonium chloride solution, extract the organic phase with methyl tert-butyl ether, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 4.05 g of compound 4 with a yield of 85%. Compound 4 is a colorless oil.

[0107] Example 3

[0108] A method for preparing bismagnolignan, comprising the following steps:

[0109] (1) Weigh compound 4 (4.07 g, 14.18 mmol, 1 equiv), compound 1 (1.3 equiv), tetrakis(triphenylphosphine)palladium(0) (0.1 equiv), and potassium carbonate (5 equiv) into a 250 mL round-bottom flask. Under nitrogen protection, add 47 mL of 1,4-dioxane and 16 mL of water. After refluxing at 95 °C for 8 h, cool to room temperature. After monitoring the reaction to completion by TLC, quench with saturated ammonium chloride solution, extract the organic phase with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 4.02 g of compound 5 with a yield of 80%. Compound 5 is a colorless oil;

[0110] (2) Weigh compound 5 (117.00 mg, 0.33 mmol, 1 equiv) into a 25 ml round-bottom flask. Under nitrogen protection, add 1.1 mL of dichloromethane and cool to -70 °C. Then, slowly add boron tribromide (5 equiv) dropwise. After slowly warming to 15 °C, continue the reaction for 2 h. After monitoring the reaction to completion by TLC, slowly pour it into ice water to quench. Extract with dichloromethane, wash with saturated brine. Dry the organic phase over anhydrous sodium sulfate and concentrate in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 83 mg of compound 6 with a yield of 85%. Compound 6 is a red oil;

[0111] (3) Weigh hydroquinone (8 equivalents) and sulfuric acid (14 equivalents) into a 100 mL round-bottom flask, add acetic acid and reflux at 110 °C. Weigh compound 6 (1.17 g, 3.93 mmol, 1 equivalent), dissolve it in a small amount of acetic acid, and add it dropwise to the above reflux solution. The concentration of compound 6 in the solution system is 0.4 mmol / mL. Continue refluxing for 15 min, then stop heating. After the system cools down and the reaction is monitored by TLC to be completed, slowly add saturated sodium bicarbonate solution to quench the reaction. Extract with dichloromethane. Wash the organic phase twice with saturated sodium bicarbonate solution and saturated brine respectively. Dry over anhydrous sodium sulfate and concentrate in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 611 mg of compound 7 with a yield of 56%. Compound 7 is a white solid;

[0112] (4) Weigh compound 7 (497 mg, 1.71 mmol) into a 100 ml round-bottom flask. Under nitrogen protection, add 20 mL of dichloromethane and stir to dissolve. Weigh anhydrous ferric chloride (28 mg, 0.17 mmol) and m-chloroperoxybenzoic acid (300 mg, 1.71 mmol) and add them. Stir at 20 °C for 1 h. After monitoring the reaction by TLC to be completed, quench with water, extract with dichloromethane. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate in vacuo. Purify the residue by ODS column chromatography (methanol and water as eluents) to obtain 320 mg of bismagnolignan with a yield of 65%. Bismagnolignan is a white solid.

[0113] The preparation method of compound 1 is as follows: Add p-allylanisole (5.0 g, 33.74 mmol, 1 equivalent) to a 100 mL dry round-bottom flask. Under a nitrogen atmosphere, add tetrahydrofuran to make the concentration of p-allylanisole in the system 0.15 mmol / mL. Stir to dissolve. Slowly add tetramethylethylenediamine (1.5 equivalents) and sec-butyllithium (2 equivalents) dropwise at -70 °C. The dropping time of sec-butyllithium is more than 10 minutes. Stir for 2 h, then naturally raise the reaction temperature to 15 °C and stir for 2 h. Then add trimethyl borate (1.5 equivalents) dropwise and stir for another 18 h. Acidify the reaction with 1 M hydrochloric acid to pH 3 and then stir for 2 h. After the reaction is completed, dilute with ethyl acetate and extract the organic phase. Wash with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuo. Purify by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 4.22 g of compound 1 with a yield of 65%. Compound 1 is a colorless solid.

[0114] The preparation method of Compound 4 is as follows: S1. Add 1,2,4-trimethoxybenzene (10 g, 59.45 mmol, 1 equivalent) into a 100 mL dry round-bottom flask. Under a nitrogen atmosphere, add tetrahydrofuran to make the concentration of 1,2,4-trimethoxybenzene in the system 0.15 mmol / mL. Stir to dissolve. Dropwise add n-butyllithium (2 equivalents) at -70 °C over a period of more than 5 minutes. After the system reacts for 20 min, naturally warm it to 15 °C and continue stirring for 1.5 h. Then cool the reaction to -70 °C again, add methyl iodide (1.5 equivalents), and slowly warm it to 15 °C and continue stirring for 2 h. After TLC detects that the reaction is complete, quench the reaction with 200 mL of saturated ammonium chloride solution. Extract the mixed system with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase with anhydrous sodium sulfate and concentrate it under reduced pressure. Purify it by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 10.73 g of Compound 2 with a yield of 99%. Compound 2 is a colorless solid;

[0115] S2. Add Compound 2 (0.95 g, 5.22 mmol, 1 equivalent) and azobisisobutyronitrile (0.2 equivalent) into a 100 mL dry round-bottom flask. Under nitrogen protection, dissolve it with carbon tetrachloride to make the concentration of Compound 2 in the system 0.2 mmol / mL, and then add N-bromosuccinimide (2.5 equivalents). Reflux at 85 °C for 12 h under light. After TLC monitors that the reaction is complete, cool it to room temperature, quench it with water, extract the organic phase with dichloromethane, wash it with saturated brine, dry it with anhydrous sodium sulfate and concentrate it under vacuum to obtain 1.59 g of Compound 3 with a yield of 89%. Compound 3 is a white solid;

[0116] S3. Add Compound 3 (5.67 g, 16.66 mmol, 1 equivalent), copper(I) iodide (0.2 equivalent) and 2,2'-bipyridine (0.2 equivalent) into a 200 mL dry round-bottom flask. Under nitrogen protection, add tetrahydrofuran to make the concentration of Compound 3 in the system 0.15 mmol / mL. Stir well, cool it to -20 °C, and dropwise add vinylmagnesium bromide (2 equivalents). Then slowly warm the reaction system to 15 °C and stir for 6 h. After TLC monitors that the reaction is complete, quench it with saturated ammonium chloride solution, extract the organic phase with methyl tert-butyl ether, wash it with saturated brine, dry it with anhydrous sodium sulfate and concentrate it under vacuum. Purify it by column chromatography (200 - 300 mesh silica gel, petroleum ether and ethyl acetate as eluents) to obtain 3.49 g of Compound 4 with a yield of 73%. Compound 4 is a colorless oil.

[0117] Comparative Example 1

[0118] The difference between the preparation method of the biphenol honokiol in this comparative example and that in Example 1 lies in the following: In step (3), hydroquinone (4.33 g, 39.32 mmol) and sulfuric acid (2 M, 16.6 mL) were weighed into a 100 mL round-bottom flask, acetic acid (15 mL) was added, and the mixture was refluxed at 115 °C. Compound 6 (1.17 g, 3.93 mmol) was weighed and dissolved in a small amount of acetic acid, and then added dropwise to the above reflux solution. After continuing to reflux for 15 min, heating was stopped. After the system cooled down and the reaction was monitored by TLC to be completed, saturated sodium bicarbonate solution was slowly added dropwise to quench the reaction. The mixture was extracted with dichloromethane. The organic phase was washed twice with saturated sodium bicarbonate solution and saturated brine respectively, dried over anhydrous sodium sulfate, and concentrated in vacuo. It was purified by column chromatography (silica gel of 200 - 300 mesh, petroleum ether and ethyl acetate as eluents) to obtain 468 mg of compound 7 with a yield of 43%. Compound 7 is a white solid; the rest are the same as in Example 1.

[0119] In the preparation method of the biphenol honokiol in this comparative example, the amount of sulfuric acid added in step (3) was reduced, and the yield of compound 7 decreased, resulting in a significant decrease in the yield of the finally prepared biphenol honokiol.

[0120] Comparative Example 2

[0121] The difference between the preparation method of the biphenol honokiol in this comparative example and that in Example 1 lies in the following: In step (1), compound 1 (3.00 g, 15.60 mmol), compound 4 (4.07 g, 14.18 mmol), tetrakis(triphenylphosphine)palladium (0.82 g, 0.71 mmol), and potassium carbonate (42.54 mmol, 5.88 g) were weighed into a 250 mL round-bottom flask. Under nitrogen protection, 47 mL of 1,4-dioxane and 16 mL of water were added. After refluxing at 70 °C for 10 h, it was cooled to room temperature. After the reaction was monitored by TLC to be complete, it was quenched with saturated ammonium chloride solution. The organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. It was purified by column chromatography (silica gel of 200 - 300 mesh, petroleum ether and ethyl acetate as eluents) to obtain 3.26 g of compound 5 with a yield of 65%. Compound 5 is a colorless oil; the rest are the same as in Example 1.

[0122] In the preparation method of the biphenol honokiol in this comparative example, the temperature of the reaction system in step (1) was reduced, and the yield of compound 5 decreased, resulting in a significant decrease in the yield of the finally prepared biphenol honokiol.

[0123] Comparative Example 3

[0124] The difference between the preparation method of the biphenol honokiol in this comparative example and that in Example 1 lies in that: in step (4), 497 mg (1.71 mmol) of compound 7 was weighed and placed in a 100 ml round-bottom flask. Under nitrogen protection, 20 mL of dichloromethane was added. After stirring to dissolve, 28 mg (0.17 mmol) of anhydrous ferric chloride was weighed and added. The mixture was stirred at 25 °C for 1 h. After monitoring the reaction by TLC and the reaction was completed, it was quenched with water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was purified by ODS column chromatography (using methanol and water as eluents) to obtain 60 mg of biphenol honokiol with a yield of 12%. The biphenol honokiol is a white solid; the rest are the same as in Example 1.

[0125] In step (4) of the preparation method of the biphenol honokiol in this comparative example, m-chloroperoxybenzoic acid was not added, resulting in a significant decrease in the yield of biphenol honokiol.

[0126] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for preparing dehydrodiconiferyl alcohol Characterized in that It includes the following steps: (1) Add compound 1 and compound 4 into a mixed solution of an organic solvent and water, and reflux at 95°C to 105°C for 8h to 12h under the action of a palladium catalyst and a carbonate to obtain compound 5; the reaction formula is as follows: (2) Dissolve the obtained compound 5 in an organic solvent, add boron tribromide at a temperature of -85°C to -70°C, and raise the temperature to 15°C to 30°C to react for 2h to 6h to obtain compound 6; the reaction formula is as follows: (3) Add hydroquinone, the obtained compound 6 and sulfuric acid into acetic acid, reflux at 110°C to 120°C for 15min to 25min, and cool to obtain compound 7; the reaction formula is as follows: (4) Carry out an oxidative coupling reaction on the obtained compound 7 under the action of a peroxide and a ferric salt to obtain the dehydrodiconiferyl alcohol; the reaction formula is as follows:

2. The method for preparing dehydrodiconiferyl alcohol according to claim 1, Characterized in that The step (1) satisfies at least one of the following: (1-1) The molar ratio of compound 4, compound 1, the palladium catalyst and the carbonate is 1:(1 to 1.3):(0.01 to 0.1):(3 to 5); (1-2) The concentration of compound 4 in the reaction solution is 0.15 mmol / mL to 0.3 mmol / mL; (1-3) The palladium catalyst is tetrakis(triphenylphosphine)palladium; (1-4) The volume ratio of the organic solvent to water in the mixed solution is (2.9 to 6):1; (1-5) The organic solvent is 1,4-dioxane, acetonitrile or a mixed solution of toluene and methanol.

3. The method for preparing dehydrodiconiferyl alcohol according to claim 1, Characterized in that The step (2) satisfies at least one of the following: (2-1) The concentration of compound 5 in the reaction solution is 0.1 mmol / mL to 0.3 mmol / mL; (2-2) The organic solvent is dichloromethane, benzene or carbon tetrachloride; (2-3) The molar ratio of compound 5 to boron tribromide is 1:(4 to 5).

4. The method for preparing dehydrodiconiferyl alcohol according to claim 1, Characterized in that The step (3) satisfies at least one of the following: (3-1) The molar ratio of compound 6, hydroquinone and sulfuric acid is 1:(8 to 12):(14 to 18); (3-2) The concentration of sulfuric acid is 2 mmol / mL to 4 mmol / mL; (3-3) The concentration of compound 6 in the reaction solution is 0.2 mmol / mL to 0.4 mmol / mL.

5. The method for preparing dehydrodiconiferyl alcohol according to claim 1, Characterized in that The step (4) satisfies at least one of the following: (4-1) The peroxide is m-chloroperoxybenzoic acid; (4-2) The ferric salt is anhydrous ferric chloride; (4-3) The solvent for the oxidative coupling reaction is dichloromethane; (4-4) The molar ratio of compound 7, the peroxide and the ferric salt is 1:(1 to 1.3):(0.1 to 0.3); (4-5) The concentration of compound 7 in the reaction solution is 0.05 mmol / mL to 0.15 mmol / mL; (4-6) The temperature of the oxidative coupling reaction is 20 °C to 30 °C, and the time is 1 h to 2 h.

6. The method for preparing bismagnolignan according to claim 1, characterized in that, The method for preparing compound 1 includes the following steps: Dissolve p-allylanisole, tetramethylethylenediamine, and sec-butyllithium in an ether solvent, stir at -85 °C to -70 °C for ortho-lithiation reaction, then raise the temperature to 15 °C to 30 °C, add trimethyl borate and stir for reaction for 18 h to 24 h, acidify with hydrochloric acid and then stir for 1 h to 2 h to obtain compound 1; The reaction general formula is as follows:

7. The method for preparing bismagnolignan according to claim 6, characterized in that, The method for preparing compound 1 satisfies at least one of the following: (5-1) The ether solvent is tetrahydrofuran; (5-2) The molar ratio of p-allylanisole, tetramethylethylenediamine, sec-butyllithium, and trimethyl borate is 1:(1 to 1.5):(1.5 to 2.0):(1 to 1.5); (5-3) The concentration of p-allylanisole in the reaction solution is 0.15 mmol / mL to 0.3 mmol / mL.

8. The method for preparing bismagnolignan according to claim 1, characterized in that, The method for preparing compound 4 includes the following steps: S1. Dissolve trimethoxybenzene and n-butyllithium in an ether solvent, stir at -85 °C to -70 °C for ortho-lithiation reaction, then add methyl iodide, raise the temperature to 15 °C to 30 °C and stir for reaction for 1 h to 2 h to obtain compound 2; 2,3,6-trimethoxytoluene; The reaction general formula is as follows: S2. Add the obtained compound 2, a radical initiator, and N-bromosuccinimide to an organic solvent, and reflux at 80 °C to 85 °C for 8 h to 12 h under light to obtain compound 3; The reaction general formula is as follows: S3. Dissolve the obtained compound 3, copper iodide, 2,2'-bipyridine, and vinylmagnesium bromide in an organic solvent, and stir at 15 °C to 30 °C for reaction for 6 h to 10 h to obtain compound 4; The reaction general formula is as follows:

9. The method for preparing bismagnolignan according to claim 8, characterized in that, Step S2 satisfies at least one of the following: (6-1) The radical initiator is azobisisobutyronitrile; (6-2) The molar ratio of compound 2, the radical initiator, and N-bromosuccinimide is 1:(0.1 to 0.2):(2.0 to 2.5); (6-3) The concentration of compound 2 in the reaction solution is 0.2 mmol / mL to 0.4 mmol / mL; (6-4) The organic solvent is carbon tetrachloride or acetonitrile.

10. The method for preparing bismagnolignan according to claim 8, characterized in that, satisfies at least one of the following: (7-1) In step S1, the ether solvent is tetrahydrofuran; (7-2) In step S1, the molar ratio of trimethoxybenzene, n-butyllithium, and methyl iodide is 1:(1.5 to 2.0):(1 to 1.5); In the step S1 described in (7-3), the concentration of 1,2,4-trimethoxybenzene in the reaction solution is 0.15 mmol / mL to 0.3 mmol / mL; In the step S3 described in (7-4), the molar ratio of the compound 3, copper(I) iodide, 2,2'-bipyridine and vinylmagnesium bromide is 1:(0.1 - 0.2):(0.1 - 0.2):(1.5 - 2.0); In the step S3 described in (7-5), the concentration of the compound 3 in the reaction solution is 0.15 mmol / mL to 0.4 mmol / mL; In the step S3 described in (7-6), the organic solvent is an ether solvent or dichloromethane.

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