A preparation method of magnolol derivatives and intermediates thereof

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for preparing a honokiol derivative and an intermediate thereof. The preparation method comprises: reacting compound M2 with ethyltriphenylphosphonium bromide under alkaline conditions to prepare a compound of formula I; allylating the compound of formula I to prepare compound M3; demethylating compound M3 under acidic conditions to prepare compound M4; and rearranging compound M4 to prepare a compound of formula II. This method utilizes readily available, inexpensive raw materials, is low cost, has simple steps, mild reaction conditions, low purification requirements, high purity, high yield, is environmentally friendly, safe, and suitable for industrial production, thus possessing significant application value.

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a honokiol derivative and an intermediate thereof. Background Art

[0002] The ability to induce angiogenesis is a prerequisite for the formation, invasion, and metastasis of malignant tumors. Tumor cells themselves and inflammatory cells (primarily macrophages) infiltrating tumor tissue and its surroundings produce a class of angiogenic factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF). These angiogenic factors promote endothelial cell division and capillary sprouting. New capillaries not only provide nutrients for tumor growth but also create favorable conditions for tumor metastasis. Therefore, angiogenesis inhibitors can be used for the prevention and treatment of most tumors, including lung cancer, liver cancer, colorectal cancer, and hemangiomas.

[0003] Honokiol, chemical formula is C 18 H 18 O2, whose chemical name is 3',5-di-2-propenyl-1,1'-biphenyl-2,4'-diphenol, has good angiostatic and anti-tumor effects, and also has anti-inflammatory, antibacterial, anti-pathogenic, anti-ulcer, antioxidant, anti-aging, and cholesterol-lowering effects.

[0004] Honokiol derivatives are reported to have similar angiostatic and antitumor effects as honokiol. Chinese Patent CN106278829A discloses a honokiol derivative with the following structure, wherein R1 and R2 are independently allyl, (E)-propenyl, (Z)-propenyl, formaldehyde, 2,3-dihydroxypropyl, 3-hydroxy-2-methoxypropyl, 2-hydroxy-3-methoxypropyl, or 2,3-epoxypropyl; and R1 and R2 are not allyl. These honokiol derivatives are used for anti-tumor and angiogenesis inhibition, exhibiting comparable effects to honokiol. These derivatives have broad application prospects in pharmaceuticals for the treatment of cancer and vascular-related diseases. Chinese Patent CN109846863B discloses the use of honokiol for the prevention or treatment of Hashimoto's thyroiditis and / or its complications in humans. Honokiol can also be replaced by structural analogs of honokiol with the same active groups.

[0005]

[0006] Chinese patent CN106278829A uses the degradation of honokiol to produce honokiol derivatives, which has a long degradation cycle. Post-processing involves high-speed countercurrent chromatography followed by column chromatography separation and final purification using semi-preparative high-performance liquid chromatography, resulting in complex procedures and low yields. Bernd Schmidt et al. published the document "Synthesis of Magnaldehydes B and E and Dictyobiphenyl B by Microwave-Promoted Cross-Coupling of Boronophenols," which discloses a synthesis method for honokiol derivatives as follows: the reaction consists of six steps: bromination, coupling, overprotection, allyl group addition, rearrangement, and deprotection. The palladium-carbon coupling requires a high temperature of 150°C, and the allyl rearrangement temperature reaches a high temperature of 250°C, making the reaction conditions harsh and the use of microwaves unfavorable for scale-up production. Deprotection of the phenolic hydroxyl group using CF3CO2H is difficult to control, complex, environmentally unfriendly, unsafe, and unsuitable for scale-up production. Furthermore, protection of the phenolic hydroxyl group after coupling can easily generate byproducts, reducing the yield.

[0007] Summary of the Invention

[0008] The object of the present invention is to provide a method for preparing honokiol derivatives and intermediates thereof with simple steps, low cost, mild reaction conditions, environmental protection, safety, and suitability for industrial production.

[0009] The present invention provides a method for preparing a compound of formula I,

[0010]

[0011] The method comprises the steps of: reacting compound M2 with ethyltriphenylphosphonium bromide under alkaline conditions to prepare a compound of formula I;

[0012] .

[0013] Preferably, the preparation method of compound M2 comprises the steps of:

[0014] (1) Compound SM1 is reacted with bromomethyl methyl ether to prepare compound M1;

[0015] ;

[0016] (2) coupling reaction of compound M1 with compound SM2 to prepare compound M2;

[0017] .

[0018] Preferably, the base used in the reaction in step (1) is triethylamine.

[0019] Preferably, the molar ratio of the compound SM1, bromomethyl methyl ether and the base is 1:(1.0-1.4):(1.5-2.0), more preferably 1:1.1:1.5.

[0020] Preferably, the solvent for the reaction in step (1) is tetrahydrofuran.

[0021] Preferably, the reaction temperature in step (1) is -5°C to 5°C, and the reaction time is 3 to 6 hours.

[0022] Preferably, the purification method of beating is adopted in step (1), and beating is further preferably carried out using a mixed solvent of petroleum ether and ethyl acetate.

[0023] Preferably, the catalyst for the coupling reaction in step (2) is Pd(OAc)2, and the ligand is 1,1'-bis(diphenylphosphino)ferrocene.

[0024] Preferably, the base for the coupling reaction in step (2) includes at least one of potassium carbonate, cesium carbonate, and potassium acetate, and potassium carbonate is more preferred.

[0025] Preferably, the molar ratio of the compound M1, base, catalyst and ligand is 1:(2~3):(0.09~0.12):(0.09~0.12).

[0026] Preferably, the molar ratio of compound M1 to compound SM2 in step (2) is 1:(1.0-1.5), more preferably 1:1.4.

[0027] Preferably, the solvent for the coupling reaction in step (2) includes a mixed solvent of N,N-dimethylformamide and water, a mixed solvent of 1,4-dioxane and water, or a mixed solvent of tetrahydrofuran and water, and more preferably a mixed solvent of tetrahydrofuran and water.

[0028] Preferably, in step (2), the coupling reaction temperature is 50-70°C, more preferably 60-65°C, and the coupling reaction time is 15-25h, more preferably 20h.

[0029] Preferably, the purification method of pulping is adopted in step (2), and pulping with a mixed solvent of petroleum ether and ethyl acetate is further preferred.

[0030] Preferably, the base includes at least one of potassium tert-butoxide, sodium tert-butoxide, and lithium diisopropylamide, and potassium tert-butoxide is more preferred.

[0031] Preferably, the phase transfer catalyst for the witiig reaction is tetrabutylammonium bromide.

[0032] Preferably, the solvent for the witiig reaction comprises at least one of N,N-dimethylformamide, dimethyl sulfoxide, and N,N-dimethylacetamide, and N,N-dimethylformamide is further preferred.

[0033] Preferably, the molar ratio of the compound M2, the base and the phase transfer catalyst is 1:(3-5):(0.04-0.06).

[0034] Preferably, the molar ratio of the compound M2 to ethyltriphenylphosphonium bromide is 1:(1.3-1.8), more preferably 1:1.5.

[0035] Preferably, the witiig reaction is: heating to 90-110° C. and reacting for 15-25 hours.

[0036] Preferably, the compound of formula I is obtained without purification after the witiig reaction.

[0037] The present invention also provides a method for preparing the compound of formula II,

[0038]

[0039] Including steps:

[0040] (a) allylating a compound of formula I to prepare compound M3, wherein the compound of formula I is prepared by the above method;

[0041] ;

[0042] (b) removing MOM from compound M3 under acidic conditions to prepare compound M4;

[0043] ;

[0044] (c) Rearrange compound M4 to prepare a compound of formula II, i.e., a honokiol derivative.

[0045] Preferably, the raw material for the allylation reaction in step (a) is allyl bromide, and the base is potassium carbonate and / or cesium carbonate, more preferably potassium carbonate.

[0046] Preferably, the molar ratio of the compound of formula I, allyl bromide and base is 1:(1-1.1):(1.5-2.2).

[0047] Preferably, the solvent for the allylation reaction in step (a) comprises at least one of acetone, acetonitrile and tetrahydrofuran, more preferably acetone.

[0048] Preferably, the allylation reaction temperature in step (a) is 35-50° C., and the reaction time is 5-8 hours.

[0049] Preferably, the acid in step (b) comprises at least one of trifluoroacetic acid, p-toluenesulfonic acid, and formic acid, more preferably formic acid.

[0050] Preferably, in step (b), the molar ratio of compound M3 to acid is 1:(8-10).

[0051] Preferably, the temperature for removing MOM in step (b) is 0-40° C., more preferably 35-40° C., and the time is 15-30 h, more preferably 24 h.

[0052] Preferably, the solvent for removing MOM in step (b) is dichloromethane.

[0053] Preferably, the raw materials for the rearrangement reaction in step (c) are diethylaluminum chloride and / or tin tetrachloride, more preferably diethylaluminum chloride.

[0054] Preferably, the molar ratio of the compound M4 to diethylaluminum chloride is 1:(0.4~1.1).

[0055] Preferably, the solvent for the rearrangement reaction in step (c) comprises at least one of dichloromethane, n-hexane, and toluene, more preferably dichloromethane.

[0056] Preferably, the rearrangement reaction in step (c) is carried out at a temperature of -5°C to 5°C and for a time of 4 to 10 hours.

[0057] Preferably, the purification in step (c) is carried out by slurrying and crystallization, and petroleum ether slurrying and n-heptane crystallization are further preferred.

[0058] The compound of formula I prepared by the present invention has a trans-E configuration structure, and the compound of formula II has a trans-E configuration structure.

[0059] The beneficial effects of the present invention are as follows:

[0060] The invention has cheap and readily available raw materials, low cost, simple steps, mild reaction conditions, low purification requirements, high purity, high yield, environmental protection, safety, suitability for industrial production, and great application value.

[0061] The total yield of the compound of formula I prepared by the present invention is above 55%, and no purification is required. The purity measured by HPLC is above 94%.

[0062] The total yield of the honokiol derivative prepared by the invention is above 31.5%, and the purity is above 96.5% as measured by HPLC. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 Compound M2 prepared in Example 1 1 HNMR detection diagram.

[0064] Figure 2 The compound of formula I prepared in Example 1 1 HNMR detection diagram.

[0065] Figure 3 Compound M3 prepared in Example 1 1 HNMR detection diagram.

[0066] Figure 4 The compound of formula II prepared in Example 1 1 HNMR detection diagram.

[0067] Figure 5 This is the HPLC detection chart of the compound of formula I prepared in Example 1.

[0068] Figure 6 This is the HPLC detection chart of the compound of formula II prepared in Example 1.

[0069] Figure 7 This is the HPLC detection chart of the compound of formula II prepared in Example 2. DETAILED DESCRIPTION

[0070] The present invention is described in more detail below by way of examples. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

[0071] In the examples of the present invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art; in the examples of the present invention, unless otherwise specified, the technical means used are conventional means well known to those skilled in the art.

[0072] The technical concept of the present invention is to use 3-bromo-4-hydroxybenzaldehyde as the starting material, protect the phenolic hydroxyl group, couple to form a biphenyl structure, form an olefin bond through a witiig reaction, then add an allyl group, deprotect and rearrange to prepare a honokiol derivative. The reaction formula is as follows:

[0073]

[0074] The specific embodiments are described as follows:

[0075] Example 1

[0076] (1) 15.00 g (74.6 mmol) of 3-bromo-4-hydroxybenzaldehyde, 11.30 g (111.9 mmol) of triethylamine, and 90 ml of tetrahydrofuran were added to a reaction flask, stirred, and cooled to 0°C. 10.25 g (82.06 mmol) of bromomethyl methyl ether was then added dropwise. After the addition was complete, the reaction was maintained at 0°C for about 4 hours. The reaction was stopped after the completion of the reaction of 3-bromo-4-hydroxybenzaldehyde by thin-layer chromatography. 180 ml of water was added to the reaction solution to quench the reaction, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic phases were combined and concentrated to a thick paste. The mixture was allowed to stand at room temperature overnight and turned into a solid. The mixture was slurried with 50 ml of a mixed solvent of petroleum ether:ethyl acetate = 6:1 (v / v). The filter cake was collected by filtration and dried to obtain 16.8 g of compound M1 (3-bromo-4-(methoxymethyl ether)benzaldehyde) as a white solid with a yield of 91.9%.

[0077] (2) Add 15.00 g (61.21 mmol) of compound M1 to a reaction flask, add 130 ml of tetrahydrofuran and 13 ml of water, then add 11.8 g (85.69 mmol) of (4-hydroxyphenyl)boric acid and 21.2 g (153.03 mmol) of potassium carbonate, start stirring, add 1.4 g (6.12 mmol) of palladium acetate and 3.4 g (6.12 mmol) of 1,1'-bis(diphenylphosphino)ferrocene, evacuate the mixture, replace the atmosphere with nitrogen three times, and then heat to 60-65°C. The reaction was stirred for 20 h. The completion of the reaction of compound M1 was confirmed by thin-layer chromatography (TLC). The product was filtered through diatomaceous earth. 390 ml of water was added to the filtrate with stirring. The product was extracted twice with 200 ml of dichloromethane. The combined organic phases were concentrated to dryness. 30 ml of a mixed solvent of petroleum ether:ethyl acetate = 4:1 (v / v) was added and the mixture was beaten at room temperature for 2 h to obtain 13.2 g of compound M2 (4'-hydroxy-6-(methoxymethyl ether)-[1,1'-biphenyl]-3-carboxaldehyde) as a light yellow solid in a yield of 83.5%.

[0078] Compound M2 1 HNMR detection diagram Figure 1 As shown, 1 H NMR (400MHz, CDCl3 ): 3.49(3H,s),5.14(1H,s),5.28(2H,s),6.93-6.96(2H,d),7.35-7.37( 1H,d),7.44-7.48(2H,m),7.83-7.86(1H,dd),7.88(1H,d),9.98(1H,s).

[0079] (3) First, add 25.87g (69.69mmol) of ethyltriphenylphosphonium bromide, 100ml of N,N-dimethylformamide, and 0.75g (2.32mmol) of tetrabutylammonium bromide into the reaction flask, cool to 0℃, and stir for 10min. Then, add 20.85g (185.84mmol) of potassium tert-butoxide, keep stirring at 0℃ for 10min, and finally add 12.00g (46.46mmol) of compound M2. After vacuuming and replacing with nitrogen three times, transfer to room temperature under nitrogen protection and stir for 30min, then heat to 95~100℃ and react for 20h. The reaction of compound M2 was confirmed to be complete by thin-layer chromatography (TLC). The temperature was lowered and the reaction solution was slowly poured into 400 ml of water. The mixture was extracted twice with 120 ml of dichloromethane. The organic phases were combined and 50 ml of 1 M sodium hydroxide solution was added to the organic phase, stirred at room temperature for 30 minutes. The layers were separated and the pH of the aqueous layer was adjusted to 5-6 by adding 1 M hydrochloric acid. The mixture was extracted twice with 100 ml of dichloromethane. The organic phases were combined and concentrated to obtain 9.2 g of compound I ((E)-2'-(methoxymethyl ether)-5'-(prop-1-en-1-yl)-[1,1'-biphenyl]-4-ol) as an oil with a yield of 73.2%. The HPLC detection chart of compound I is shown in FIG. Figure 5 As shown, the purity is 94.65%.

[0080] Compounds of formula I 1 HNMR detection diagram Figure 2 As shown, 1 H NMR (400MHz, CDCl3 ): 1.90-1.92(3H,dd),3.43(3H,s),5.13(2H,s),6.15-6.24(1H,m),6.40-6.44(1H,dd,J=15.8Hz) ,6.90-6.92(2H,dd),7.15-7.17(1H,d),7.25-7.28(1H,dd),7.31-7.32(1H,d),7.44-7.46(2H,d).

[0081] (4) Add 9.00 g (33.29 mmol) of the compound of formula I to a flask, add 40 ml of acetone and stir to dissolve, then add 9.2 g (66.58 mmol) of potassium carbonate, and slowly add 4.23 g (34.95 mmol) of allyl bromide at room temperature. After the addition is complete, raise the temperature to 40-45°C and react for about 6 hours. The reaction of the compound of formula I is confirmed by thin layer chromatography (TLC). Add 100 ml of water to quench the reaction, extract with 50 ml of dichloromethane twice, wash with 10% brine, separate the layers, and concentrate the organic phase to dryness to obtain 9.6 g of compound M3 ((E)-4'-(allyloxy)-2-(methoxymethyl ether)-5-(prop-1-en-1-yl)-1,1'-biphenyl) as an oily substance with a yield of 92.8%.

[0082] Compound M3 1 HNMR detection diagram Figure 3 As shown, 1 H NMR (400MHz, CDCl3 ): 1.89-1.91(3H,dd),3.42(3H,s),4.61-4.62(2H,d),5.12(2H,s),5.33-5.35(1H,dd),5.45-5.50(1H,dd),6.08-6.22(2H, m),6.39-6.43(1H,dd,J=15.6Hz),6.99-7.01(2H,d),7.14-7.16(1H,d),7.24-7.27(1H,dd),7.31(1H,d),7.47-7.50(2H,d).

[0083] (5) Compound M3 (9.00 g, 28.99 mmol) was added to a flask and dissolved in 30 ml of dichloromethane. 10 ml of formic acid was added at room temperature and the temperature was raised to 35-40°C with stirring for 24 h. The reaction of Compound M3 was confirmed to be complete by thin layer chromatography (TLC). 15 ml of water was added to quench the reaction. The organic phase was separated and washed twice with 15 ml of water and then once with 10 ml of saturated sodium bicarbonate solution. The organic phase was concentrated to obtain 6.1 g of Compound M4 ((E)-4'-(allyloxy)-5-(prop-1-en-1-yl)-[1,1'-biphenyl]-2-ol) as an oil with a yield of 79%.

[0084] (6) Dissolve 6.00 g (22.55 mmol) of compound M4 in 60 ml of dichloromethane, cool to 0°C, and slowly add 20 ml of diethylaluminum chloride (1.0 M n-hexane solution). Maintain stirring at 0°C for about 6 h. The reaction of compound M4 was confirmed to be complete by thin layer chromatography. 20 ml of water was added to quench the reaction. The layers were separated. The aqueous layer was extracted twice with 20 ml of dichloromethane. The organic phases were combined and stirred for 30 min by adding 30 ml of 1 M sodium hydroxide solution. The layers were separated. The pH of the aqueous layer was adjusted to 5 with 1 M hydrochloric acid solution. 50 ml of dichloromethane was added and extracted twice. The organic phases were combined, dried, concentrated to dryness, and petroleum ether was added and beaten at room temperature for 2 hours to obtain a solid. The solid was filtered and 85 ml of n-heptane was added to the filter cake and refluxed to dissolve. The solid was precipitated by cooling. The solid was filtered and dried to obtain 4.6 g of compound II ((E)-3'-allyl-5-(prop-1-en-1-yl)-[1,1'-biphenyl]-2,4'-diphenol) with a yield of 76.6%. The HPLC detection chart of compound II is shown in FIG. Figure 6 As shown, the purity is 96.95%.

[0085] Compounds of formula II 1 HNMR detection diagram Figure 4 As shown,1 H NMR(400MHz,MeOD): 1.85-1.87(3H,dd),3.41-3.43(2H,d),5.02-5.05(1H,dd),5.08-5.13(1H,dd),6.01-6.15(2H,m) ,6.34-6.38(1H,dd,J=15.8Hz),6.79-6.84(2H,t),7.11-7.14(1H,dd),7.17(1H,d),7.23-7.26(1H,dd),7.27(1H,d).

[0086] Example 2

[0087] (1) 200.00 g (0.995 mol) of 3-bromo-4-hydroxybenzaldehyde, 150.9 g (1.492 mol) of triethylamine, and 800 ml of tetrahydrofuran were added to a reaction flask, stirred, and cooled to 0°C. 136.7 g (1.094 mol) of bromomethyl methyl ether was then added dropwise. After the addition was complete, the temperature was maintained at 0°C for about 5 h. The reaction was stopped after the completion of the reaction of 3-bromo-4-hydroxybenzaldehyde by thin-layer chromatography. 1.6 L of water was added to the reaction solution to quench the reaction. The solution was extracted twice with 1 L of ethyl acetate, and the organic phase was collected and concentrated to a thick paste. The thick paste was left at room temperature overnight to become a solid. The paste was slurried with 400 ml of a mixed solvent of petroleum ether:ethyl acetate = 6:1 (v / v). The filter cake was collected by filtration and dried to obtain 226.3 g of compound M1 (3-bromo-4-(methoxymethyl ether)benzaldehyde) as a white solid with a yield of 92.8%.

[0088] (2) Add 220.00 g (0.898 mol) of compound M1 to the reaction flask, add 1.3 L of tetrahydrofuran and 130 ml of water, then add 173.4 g (1.257 mol) of (4-hydroxyphenyl)boric acid and 310.3 g (2.245 mol) of potassium carbonate, start stirring, add 20.2 g (0.089 mol) of palladium acetate and 49.3 g (0.089 mol) of 1,1'-bis(diphenylphosphino)ferrocene, evacuate the flask, replace the atmosphere with nitrogen three times, and then heat to 60-65 The reaction was stirred at 4°C for 22 h. The reaction of compound M1 was confirmed by thin-layer chromatography (TLC) spot plate. The product was filtered through diatomaceous earth. 2.6 L of water was added to the filtrate with stirring. The product was extracted twice with 1 L of dichloromethane. The combined organic phases were concentrated to dryness. 600 ml of a mixed solvent of petroleum ether:ethyl acetate = 4:1 (v / v) was added and the mixture was beaten at room temperature for 2 h to obtain 188.7 g of compound M2 (4'-hydroxy-6-(methoxymethyl ether)-[1,1'-biphenyl]-3-carbaldehyde) as a light yellow solid in a yield of 81.4%.

[0089] (3) First, add 366.4 g (0.987 mol) of ethyltriphenylphosphonium bromide, 1.5 L of N,N-dimethylformamide, and 10.6 g (32.9 mmol) of tetrabutylammonium bromide into the reaction flask, cool to 0 °C, and stir for 10 min. Then, add 295.3 g (2.632 mol) of potassium tert-butoxide, keep stirring at 0 °C for 10 min, and finally add 170.00 g (0.658 mol) of compound M2. After vacuuming and replacing with nitrogen three times, transfer to room temperature under nitrogen protection and stir for 30 min. Then, heat to 95~100 °C and react for 22 h. Completion of the reaction of compound M2 was confirmed by thin-layer chromatography (TLC). The temperature was lowered and the reaction solution was slowly poured into 5 L of water. The mixture was extracted with 1 L of dichloromethane three times. The organic phases were combined, and 700 ml of 1 M sodium hydroxide solution was added to the organic phase, followed by stirring at room temperature for 30 min. The layers were separated, and the pH of the aqueous layer was adjusted to 5-6 by adding 1 M hydrochloric acid. The mixture was then extracted with 1 L of dichloromethane twice. The organic phases were combined and concentrated to obtain 131.4 g of compound of formula I ((E)-2'-(methoxymethyl ether)-5'-(prop-1-en-1-yl)-[1,1'-biphenyl]-4-ol) as an oil in a yield of 73.8%.

[0090] (4) 130.00 g (0.481 mol) of the compound of formula I was added to a flask, 600 ml of acetone was added, and the mixture was stirred and dissolved. 132.9 g (0.962 mol) of potassium carbonate was then added, and 61.1 g (0.505 mol) of allyl bromide was slowly added at room temperature. After the addition was complete, the temperature was raised to 40-45°C and the reaction was continued for about 7 hours. The reaction of the compound of formula I was confirmed to be complete by thin layer chromatography. 1.5 L of water was added to quench the reaction, and the mixture was extracted twice with 800 ml of dichloromethane. The mixture was washed with 10% brine, separated, and the organic phase was concentrated to dryness to obtain 143.6 g of compound M3 ((E)-4'-(allyloxy)-2-(methoxymethyl ether)-5-(prop-1-en-1-yl)-1,1'-biphenyl) as an oily substance with a yield of 96.2%.

[0091] (5) Compound M3 (140.00 g, 0.451 mol) was added to a flask and dissolved in 500 ml of dichloromethane. 170 ml of formic acid was added at room temperature and the temperature was raised to 35-40°C with stirring for 24 h. The reaction of Compound M3 was confirmed to be complete by thin layer chromatography (TLC). 250 ml of water was added to quench the reaction. The organic phase was separated and washed twice with 250 ml of water and once with 200 ml of saturated sodium bicarbonate solution. The organic phase was concentrated to obtain 97.5 g of Compound M4 ((E)-4'-(allyloxy)-5-(prop-1-en-1-yl)-[1,1'-biphenyl]-2-ol) as an oil with a yield of 81.2%.

[0092] (6) Dissolve 95.00 g (0.357 mol) of compound M4 in 500 ml of dichloromethane, cool to 0°C, and slowly add 150 ml of diethylaluminum chloride (1.0 M n-hexane solution). Maintain stirring at 0°C for about 8 h. The reaction of compound M4 was confirmed to be complete by thin layer chromatography. 200 ml of water was added to quench the reaction, the layers were separated, and the aqueous layer was extracted twice with 500 ml of dichloromethane. The organic phases were combined and stirred for 30 minutes with 1 L of 1M sodium hydroxide solution. The layers were separated, and the pH of the aqueous layer was adjusted to 5 with 1M hydrochloric acid solution. 500 ml of dichloromethane was added twice and extracted. The organic phases were combined, dried, concentrated to dryness, and petroleum ether was added and beaten at room temperature for 2 hours to obtain a solid. The solid was filtered and 1.2 L of n-heptane was added to the filter cake and refluxed to dissolve it. The solid was precipitated by cooling and filtering to obtain 75.4 g of compound II ((E)-3'-allyl-5-(prop-1-en-1-yl)-[1,1'-biphenyl]-2,4'-diphenol) with a yield of 79.4%. The HPLC detection chart of compound II is shown below. Figure 7 As shown, the purity is 97.14%.

[0093] It is important to note that the above embodiments are intended only to further illustrate and describe the technical solutions of the present invention and are not intended to further limit the technical solutions of the present invention. The methods of the present invention are merely preferred implementations and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula II, characterized in that Including steps: (1) Compound SM1 is reacted with bromomethyl methyl ether to prepare compound M1; ； (2) Compound M1 is coupled with compound SM2 to prepare compound M2, wherein the catalyst of the coupling reaction is Pd(OAc)2, the ligand is 1,1'-bis(diphenylphosphino)ferrocene, the base is at least one of potassium carbonate, cesium carbonate, and potassium acetate, the solvent is a mixed solvent of N,N-dimethylformamide and water, a mixed solvent of 1,4-dioxane and water, or a mixed solvent of tetrahydrofuran and water, the coupling reaction temperature is 50-70°C, and the coupling reaction time is 15-25h; ； (3) Compound M2 is reacted with ethyltriphenylphosphonium bromide under alkaline conditions to prepare a compound of formula I; the base is at least one of potassium tert-butoxide, sodium tert-butoxide, and lithium diisopropylamide; the phase transfer catalyst of the witig reaction is tetrabutylammonium bromide, and the solvent is at least one of N,N-dimethylformamide, dimethyl sulfoxide, and N,N-dimethylacetamide; the molar ratio of compound M2, base, and phase transfer catalyst is 1:3-5:0.04-0.06; the molar ratio of compound M2 to ethyltriphenylphosphonium bromide is 1:1.3-1.8; the witig reaction is: heating to 90-110°C and reacting for 15-25 hours; ； (4) performing an allylation reaction on the compound of formula I to prepare compound M3; ； (5) Compound M3 is de-MOMed under acidic conditions to prepare Compound M4, wherein the acid is formic acid and the molar ratio of Compound M3 to the acid is 1:8-10; ； (6) Compound M4 is subjected to a rearrangement reaction to prepare a compound of formula II, wherein the raw materials for the rearrangement reaction are diethylaluminum chloride and / or tin tetrachloride, the rearrangement reaction temperature is -5°C to 5°C, and the reaction time is 4 to 10 hours.

2. The method according to claim 1, characterized in that The base used in the reaction in step (1) is triethylamine, and the solvent is tetrahydrofuran; the molar ratio of compound SM1, bromomethyl methyl ether, and base is 1:1.0-1.4:1.5-2.0; the reaction temperature is -5°C-5°C, and the reaction time is 3-6 hours.

3. The method according to claim 1, characterized in that In step (2), the molar ratio of compound M1, base, catalyst and ligand is 1:2~3:0.09~0.12:0.09~0.12; the molar ratio of compound M1 to compound SM2 is 1:1.0~1.

5.

4. The method according to claim 1, wherein In the step (4), the raw materials for the allylation reaction are allyl bromide, the base is potassium carbonate and / or cesium carbonate, and the solvent includes at least one of acetone, acetonitrile, and tetrahydrofuran; the molar ratio of the compound of formula I, allyl bromide, and the base is 1:1-1.1:1.5-2.2; the allylation reaction temperature is 35-50° C., and the reaction time is 5-8 hours.

5. The method according to claim 1, wherein In the step (5), the temperature for removing MOM is 0-40° C., the time is 15-30 h, and the solvent is dichloromethane.

6. The method according to claim 1, characterized in that The solvent for the rearrangement reaction in step (6) includes at least one of dichloromethane, n-hexane, and toluene; and the molar ratio of compound M4 to diethylaluminum chloride is 1:0.4-1.1.

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