CN118146072A - Preparation method of honokiol and intermediate thereof - Google Patents

Preparation method of honokiol and intermediate thereof Download PDF

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CN118146072A
CN118146072A CN202410565320.5A CN202410565320A CN118146072A CN 118146072 A CN118146072 A CN 118146072A CN 202410565320 A CN202410565320 A CN 202410565320A CN 118146072 A CN118146072 A CN 118146072A
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butyl
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CN118146072B (en
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葛建华
陈逢春
王德勇
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Beijing Jinrui Jiye Pharmaceutical Technology Co ltd
CHENGDU JINRUI JIYE BIO-TECHNOLOGY CO LTD
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Beijing Jinrui Jiye Pharmaceutical Technology Co ltd
CHENGDU JINRUI JIYE BIO-TECHNOLOGY CO LTD
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a preparation method of honokiol and an intermediate thereof. The preparation method comprises the following steps: the compound SM1 and the compound SM2 are subjected to coupling reaction in the presence of a catalyst and oxygen to prepare an intermediate 1, tert-butyl is removed under an acidic condition to obtain a compound of a formula I, the compound of the formula I, alkali and butyl chloroformate are reacted to obtain an intermediate 2, then the intermediate 2 is reacted with allyl tributylstannane in the presence of the catalyst to obtain an intermediate 3, and finally butyl is decarbonized under the alkali condition to obtain honokiol. The method has the advantages of simple steps, low equipment requirement, low cost, low toxicity, environmental protection, safety, low purification requirement, suitability for industrial production and great application value.

Description

Preparation method of honokiol and intermediate thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a preparation method of honokiol and an intermediate thereof.
Background
Honokiol (Honokiol) with a chemical formula of C 18H18O2 and a chemical name of 3', 5-di-2-propenyl-1, 1' -biphenyl-2, 4' -diphenol has obvious and durable pharmacological effects of central muscle relaxation, central nerve inhibition, anti-inflammatory, antibacterial, anti-pathogenic microorganism, anti-ulcer, anti-oxidation, anti-aging, anti-tumor, cholesterol reduction and the like; can be used for treating acute enteritis, bacillary or amebic dysentery, and chronic gastritis. The honokiol has remarkable antibacterial activity on gram-positive bacteria, acid-resistant bacteria and filamentous fungi, has more remarkable antibacterial effect on streptococcus mutans and has the strongest inhibitory effect on staphylococcus. The medicine is mainly used for eliminating chest and abdomen fullness, calming central nerves, relaxing muscle of athletes, resisting fungi, resisting ulcer and the like clinically. In addition, the new application of honokiol can be expanded to mental diseases.
The Chinese patent CN108430463A adopts the modes of coupling, tertiary butyl removal, phenolic hydroxyl methyl esterification, upper bromine, upper allyl and demethylation to prepare honokiol, the method uses virulent or cancerogenic agents such as dimethyl sulfate and carbon tetrachloride solution, can cause irreversible damage to human bodies, also uses boron tribromide, has great potential safety hazard in industrialized use, and has multi-step high-temperature and ultralow-temperature reaction, has high requirements on equipment, adopts column chromatography in the preparation process, increases a large amount of cost, is neither economical nor environment-friendly, can cause large fluctuation of quality of each intermediate and honokiol, and is difficult to realize industrialization. KENICHI HARADA et al, publication EFFICIENT SYNTHESIS of neurotrophic honokiol using Suzuki-Miyaura Reactions discloses that coupling is performed firstly, then bromine and phenolic hydroxyl groups are protected by acetic anhydride, and finally allyl groups are added, and then deprotection groups are carried out to prepare honokiol; in addition, the conventional purification method is difficult to realize, each intermediate is obtained by column chromatography in the whole preparation process, a large amount of cost is increased, and industrialization is difficult to realize.
Disclosure of Invention
The invention aims to provide the preparation method of honokiol and the intermediate thereof, which has the advantages of simple steps, low cost, environmental protection, safety and suitability for industrial production.
The present invention provides a process for the preparation of a compound of formula I,
The method comprises the following steps:
(1) The compound SM1 and the compound SM2 are subjected to coupling reaction in the presence of a catalyst and oxygen atmosphere to prepare an intermediate 1,
；
(2) Intermediate 1 is subjected to tert-butyl removal under acidic conditions to prepare a compound of formula I.
Preferably, the catalyst in the step (1) is Cr-Salen-Cy.
Preferably, the molar ratio of compound SM1 to compound SM2 in step (1) is 1: (1.0 to 1.5), more preferably 1:1.2.
Preferably, the molar ratio of compound SM1 to catalyst in step (1) is 1: (0.020 to 0.030), more preferably 1:0.025.
Preferably, the solvent for the coupling reaction in the step (1) is selected from one or more of toluene, N-dimethylformamide and 1, 4-dioxane, and more preferably toluene.
Preferably, the coupling reaction temperature in the step (1) is 60 to 110 ℃, more preferably 60 to 70 ℃, and the coupling reaction time is 10 to 16 hours, more preferably 12 hours or 16 hours.
Preferably, in step (1), a purification mode of crystallization and beating is adopted.
Preferably, the solvent used for the crystallization is n-heptane; the solvent used for beating is a mixed solvent of ethyl acetate and n-heptane.
Preferably, the acidic condition in step (2) is the use of aluminum trichloride and/or methanesulfonic acid, more preferably methanesulfonic acid.
Preferably, the molar ratio of intermediate 1 to methanesulfonic acid is 1: (8-12), further preferably 1:10.
Preferably, the solvent for removing tert-butyl in the step (2) is selected from one or more of toluene, N-dimethylformamide and 1, 4-dioxane, and more preferably toluene.
Preferably, the temperature for removing the tert-butyl in the step (2) is 20-60 ℃, more preferably 20-30 ℃ for 7-8 hours, more preferably 7 hours or 8 hours.
Preferably, step (2) adopts a pulping purification mode, and further preferably, methyl tertiary butyl ether is subjected to reflux pulping.
The invention also provides a preparation method of honokiol, which comprises the following steps:
(a) Reacting a compound of formula I, a base and butyl chloroformate to obtain an intermediate 2,
；
(B) Reacting the intermediate 2 with allyl tributylstannane in the presence of a catalyst to obtain an intermediate 3,
；
(C) Intermediate 3 decarbonizes butyl ester under alkaline condition to obtain honokiol.
Preferably, the compound of formula I in step (a) is prepared by the process described above.
Preferably, the alkali in the step (a) is selected from one or more of potassium carbonate, sodium carbonate and sodium hydroxide, and further preferably potassium carbonate.
Preferably, the molar ratio of the compound of formula i, base to butyl chloroformate in step (a) is 1: (2.5 to 3.5): (2-3), further preferably 1:3:2.5.
Preferably, the solvent reacted in the step (a) is selected from one or more of tetrahydrofuran, N-dimethylformamide and 1, 4-dioxane, and further preferably N, N-dimethylformamide.
Preferably, the reaction temperature in step (a) is 50 to 60 ℃, and the reaction time is 6 to 7 hours, more preferably 6 hours or 7 hours.
Preferably, step (a) employs a crystalline purification mode, and more preferably, a mixed solvent of ethyl acetate and n-heptane is crystallized.
Preferably, the catalyst in step (b) is bis (triphenylphosphine) palladium dichloride.
Preferably, the molar ratio of intermediate 2, catalyst and allyl tributylstannane in step (b) is 1: (0.02-0.08): (2.0 to 2.5), more preferably 1:0.05:2.2.
Preferably, the reaction solvent in step (b) is selected from 1, 4-dioxane and/or N, N-dimethylformamide, further preferably 1, 4-dioxane.
Preferably, the reaction temperature in step (b) is 60 to 100 ℃, more preferably 60 to 70 ℃, and the reaction time is 1 to 2 hours, more preferably 1.0 hour or 2 hours.
Preferably, the base in step (c) is sodium hydroxide and/or potassium hydroxide, more preferably potassium hydroxide.
Preferably, the solvent of butyl decarbonate in the step (c) is selected from one or more of ethanol, tetrahydrofuran and acetonitrile, and further preferably acetonitrile.
Preferably, the temperature of the butyl decarbonate in the step (c) is 0 to 30 ℃, more preferably 0 to 10 ℃, and the time is 3 to 5 hours, more preferably 3 hours or 5 hours.
Preferably, step (c) employs a crystalline purification scheme, with n-heptane crystallization being further preferred.
The chemical name of the Cr-Salen-Cy related by the invention is (1S, 2S) - (+) - [1, 2-cyclohexane diamine-N, N' -bis (3, 5-di-tert-butylsalicylidene) ] chromium chloride.
The beneficial effects of the invention are as follows:
The method has the advantages of simple steps, low equipment requirement, low cost, low toxicity, environmental protection, safety, low purification requirement, suitability for industrial production and great application value.
The total yield of the compound of the formula I is more than 64%, and the purity of the compound of the formula I is more than 98.1% as measured by HPLC.
The total yield of the prepared honokiol is more than 33.5%, the purity of the product prepared in each step is more than 97.5% measured by HPLC, and the purity of the honokiol is more than 99.9% measured by HPLC.
Drawings
FIG. 1 is a nuclear magnetic resonance chart of intermediate 1 prepared in example 1.
FIG. 2 is a nuclear magnetic resonance diagram of the compound of formula I prepared in example 1.
FIG. 3 is a nuclear magnetic resonance chart of intermediate 3 prepared in example 1.
FIG. 4 is a HPLC detection chart of honokiol prepared in example 1.
FIG. 5 is a nuclear magnetic pattern of honokiol prepared in example 1.
Detailed Description
The present invention will be described in more detail with reference to examples. The following examples are given for illustrative purposes and are not intended to limit the scope of the invention.
In the examples of the present invention, all raw material components are commercially available products well known to those skilled in the art unless specified otherwise; in the embodiments of the present invention, unless specifically indicated, all technical means used are conventional means well known to those skilled in the art.
The technical conception of the invention is that 2-tertiary butyl-4-bromophenol and 2-bromine-6-tertiary butylphenol are adopted as raw materials to prepare honokiol through three steps of reaction, one step of upper protection and one step of deprotection, and the reaction formula is as follows:
Specific examples are as follows:
example 1
Step 1: 18.0g (78.56 mmol) of compound SM1 (2-tert-butyl-4-bromophenol) and 21.6g (94.27 mmol) of compound SM2 (2-bromo-6-tert-butylphenol) were weighed into a reaction flask, 200ml of toluene was added, 1.23g of Cr-Salen-Cy (1.96 mmol) was added under uniform stirring, the mixture was evacuated and replaced three times with oxygen, the reaction was then allowed to proceed at 60 to 70℃under an oxygen atmosphere, the reaction was stopped by thin layer chromatography and spot-plating, the reaction was stopped, a saturated aqueous sodium bicarbonate solution was added to the reaction solution and washed (20 ml/2 x) and the organic phase was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was stirred for 2h at 10-20 ℃ with 60ml of n-heptane for crystallization, filtered, and the filter cake was slurried with 40ml of a mixture of ethyl acetate and n-heptane (ethyl acetate: n-heptane=1:10) for 2h, filtered, and the filter cake dried to give 28.5g of intermediate 1 as a white solid with a purity of 97.68% and a yield of 79.5%.
The nuclear magnetic pattern of intermediate 1 is shown in FIG. 1, 1H NMR (400 MHz, DMSO-d 6): 1.36-1.42 (18H), 7.17-7.19 (1H), 7.23-7.24 (1H), 7.30 (1H), 7.47 (1H).
Step 2: 25.0g (54.80 mmol) of intermediate 1 is weighed, 100ml of toluene is added, 52.7g (548.0 mmol) of methanesulfonic acid is added dropwise under uniform stirring, the mixture is uniformly stirred for 7 hours at 20-30 ℃, the completion of the reaction is confirmed by thin layer chromatography spot plate, water is added for washing (100 ml/time) 3 times, an organic phase is washed (50 ml/time) by saturated sodium bicarbonate aqueous solution, 50ml of saturated brine is used for washing, then the organic phase is dried by sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, 80ml of methyl tertiary butyl ether is added into the crude product, the mixture is stirred under reflux for 2 hours, then the mixture is slowly cooled to room temperature and filtered, and the compound of the formula I is obtained, wherein the compound is 15.2g of white-like solid, the purity is 98.19%, and the yield is 80.6%.
The nuclear magnetic diagram of the compound of formula I is shown in figure 2 ,1H NMR(400MHz,DMSO-d6)：6.88-6.91(1H),6.99-7.01(1H),7.28-7.31(1H),7.36-7.39(2H),7.68-7.69(1H),9.88(1H),10.33(1H).
Step 3: 14.0g of the compound of formula I (40.70 mmol) is taken, 70ml of N, N-dimethylformamide, 16.9g (121.10 mmol) of potassium carbonate and 13.9g (101.75 mmol) of butyl chloroformate are added, the temperature is raised to 50-60 ℃ under the protection of nitrogen, the reaction is carried out for 6 hours, and the reaction liquid is cooled to the room temperature after the completion of TLC monitoring. The reaction was quenched by adding 210ml water and the product extracted with ethyl acetate (70 ml/3 x). The combined organic phases were washed with water (50 ml/2 times) and once with 50ml saturated brine. The organic phase was dried over sodium sulfate, concentrated under reduced pressure at 40℃until no liquid was dropped, 5ml of ethyl acetate and 30ml of n-heptane were added thereto, stirred and crystallized at ordinary temperature for 3 hours, and filtered to give intermediate 2 as an off-white solid 17.5g, yield 78.9%, purity 97.78%.
Step 4: 17.0g (31.24 mmol) of intermediate 2 was weighed, 170ml of 1, 4-dioxane was added, 22.76g (68.73 mmol) of allyl tributylstannane, 1.1g (1.56 mmol) of bis (triphenylphosphine) palladium dichloride was added, the reaction was carried out under nitrogen protection after three times of vacuum nitrogen substitution, the temperature was raised to 60-70 ℃ for 1.0h, and the completion of the reaction of intermediate 3 was confirmed by thin layer chromatography plate chromatography. The reaction mixture was cooled, 340ml of water was added to the reaction mixture, the ethyl acetate extract (50 ml/2 x) was added, and the organic phase was washed with 50ml of saturated brine and separated. The organic phase was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, to give 11.3g of intermediate 3 as a pale yellow oil in 77.5% yield and 97.53% purity.
The nuclear magnetic pattern of intermediate 3 is shown in FIG. 3 ,1H NMR(400MHz,DMSO-d6 )：0.91-0.95（3H）,1.00-1.04(3H),1.30-1.38(2H),1.48-1.54（2H）,1.58-1.63(2H),1.74-1.81(2H),3.39-3.48(4H),4.03-4.19（2H）,4.29-4.32(2H),5.10-5.19(4H),5.92-6.07(2H),7.16-7.28(4H),7.35-7.38(2H).
Step 5: taking 11.0g (23.57 mmol) of intermediate 3, adding 35ml of acetonitrile for dissolution, cooling to 0-10 ℃, adding 30ml of 10% potassium hydroxide solution, maintaining the temperature, stirring for reaction for 3h, adding 1N hydrochloric acid solution into the reaction solution to adjust the pH value to about 7 after the monitored raw materials react, precipitating solid, filtering, and leaching a filter cake with N-heptane (10 ml/time is 2 times). And adding 66ml of n-heptane into the filter cake, heating and refluxing until the filter cake is completely dissolved, slowly cooling to room temperature, standing and crystallizing for 8 hours, filtering and drying. 5.4g of honokiol is obtained as a white solid. As shown in fig. 4, purity was 99.94% by HPLC; the yield thereof was found to be 85.9%.
The nuclear magnetic diagram of honokiol is shown in figure 5 ,1H NMR(400MHz ,CDCl3 )：3.34-3.35(2H),3.46-3.47(2H),5.04-5.10(4H),5.18-5.23(2H),5.94-5.99(1H),6.01-6.06(1H),6.89-6.92(2H),7.02(1H),7.04-7.06(1H),7.20-7.23(2H).
Example 2
Step 1: 500.0g (2.18 mol) of compound SM1 (2-tert-butyl-4-bromophenol) and 600.3g (2.62 mol) of compound SM2 (2-bromo-6-tert-butylphenol) are weighed into a reaction flask, 34.5g of Cr-Salen-Cy (54.5 mmol) is added under uniform stirring by adding 10L of toluene, the mixture is vacuumized and replaced by oxygen for three times, then the mixture is reacted for 16 hours at 60-70 ℃ under the oxygen atmosphere, the reaction is stopped after confirming that the reaction of 2-tert-butyl-4-bromophenol is completed by a thin layer chromatography spot plate, the reaction solution is cooled to room temperature, saturated sodium bicarbonate aqueous solution is added into the reaction solution for washing (0.5L/2 times), and the organic phase is dried by using 750ml of saturated brine and filtered and concentrated under reduced pressure to remove the solvent. 1.5L of n-heptane is added, stirred and crystallized for 3 hours at the temperature of 10-20 ℃, filtered, and the filter cake is pulped for 2 hours by using 1L of a mixed solvent of ethyl acetate and n-heptane (ethyl acetate: n-heptane=1:10), so as to obtain 776.3g of intermediate 1, white solid with the purity of 97.98 percent and the yield of 78.1 percent.
Step 2: weighing 750.0g (1.64 mol) of intermediate 1, adding 3L of toluene for dissolution, dripping 1581.0g (16.40 mol) of methanesulfonic acid at 20-30 ℃, maintaining the temperature after dripping, stirring for reaction for 8 hours, adding water for washing (3L/3 times) after the completion of the reaction of a thin-layer chromatography spot plate, washing an organic phase with saturated sodium bicarbonate aqueous solution (1.5L/2 times), washing the organic phase with 1.5L of saturated saline, drying sodium sulfate, filtering, concentrating under reduced pressure to remove the solvent, obtaining a crude product, adding 2.4L of methyl tertiary butyl ether, refluxing and pulping for 2 hours, slowly cooling, and filtering. The compound of formula I was obtained as an off-white solid 479.5g, 98.27% purity, 85.0% yield.
Step 3: 450.0g (1.31 mol) of the compound shown in the formula I is taken, 2.2L of N, N-dimethylformamide is added, 543.1g (3.93 mol) of potassium carbonate is added, 448g (3.28 mol) of butyl chloroformate is added, the temperature is increased by 50 to 60 ℃ under the protection of nitrogen, the reaction is carried out for 7 hours, and the reaction liquid is cooled to the room temperature after the completion of TLC monitoring. The reaction was quenched by addition of 6.6L water and extracted 2.2L/3 times with ethyl acetate. The combined organic phases were washed with water (1.3L/2 x) and once with 1.3L saturated brine. The organic phase was dried over sodium sulfate, concentrated under reduced pressure at 40℃until no liquid was dropped, and 160ml of ethyl acetate and 1L of n-heptane were added thereto, followed by stirring and crystallization at room temperature for 5 hours, followed by filtration. Intermediate 2 was obtained as off-white solid 568.3g in 79.7% yield. The purity is 97.97 percent.
Step 4: 550g (1.01 mol) of intermediate 2 was weighed, 5L of 1, 4-dioxane was added, 735.09g (2.22 mol) of allyl tributylstannane, 35.1g (0.05 mol) of bis (triphenylphosphine) palladium dichloride was added, the reaction was completed by heating up to 60-70 ℃ for 2h under nitrogen protection after three times of vacuum nitrogen replacement, and the completion of the reaction of intermediate 3 was confirmed by thin layer chromatography by a spot plate. The reaction solution was cooled, 10L of water was added dropwise to the reaction system, ethyl acetate was added to extract the product (2L/2 x), and the organic phase was washed with 1.5L of saturated brine and separated. The organic phase is dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure to remove the solvent. The intermediate 3 was obtained as a pale yellow oil in a total amount of 379.8g, yield 80.6% and purity 97.86%.
Step 5: adding 370g (0.79 mol) of intermediate 3 into 1.2L of acetonitrile for dissolution, cooling to 0-10 ℃, adding 1.1L of 10% potassium hydroxide solution, maintaining the temperature for stirring reaction for 5h, adding 1N hydrochloric acid solution into the reaction solution to adjust the pH value to about 7 after the monitored raw materials react, precipitating solid, filtering, and leaching a filter cake with N-heptane (350 ml/time 2 times). And adding 2.2L of n-heptane into the filter cake, heating and refluxing until the filter cake is completely dissolved, slowly cooling to room temperature in a static state for crystallization for 9 hours, filtering and drying. 183.4g of honokiol was obtained as a white solid. Purity 99.91% and yield 87.1%.
Comparative example 1
Referring to examples 1 to 5 of chinese patent CN108430463a, the specific synthetic route is as follows:
First step
To a 100ml flask equipped with a reflux condenser were added 2-tert-butyl-6-methylphenol (657 mg,4.0 mmol), 2-tert-butyl-4-methylphenol (788 mg,4.8 mmol), cr-Salen-Cy catalyst (63 mg,0.1 mmol) and distilled toluene (20 mL, 0.2M). The reaction mixture was purged with oxygen and heated to 90 ℃ under an oxygen atmosphere for 20h. The mixture was cooled to ambient temperature. To a solution of the compound (3, 3 '-di-tert-butyl-5, 5' -dimethyl- [1,1 '-biphenyl ] -2,4' -diol) was slowly added aluminum chloride (1.1 g,8.8 mmol) over 5 minutes at 0 ℃ and the mixture was warmed to ambient temperature over 30 minutes. After stirring for a further 2 hours at ambient temperature, the reaction mixture was quenched by adding 30ml of 1n HCl solution at 0 ℃. The mixture was then extracted thoroughly with dichloromethane (2X 20 mL). The combined organic layers were concentrated by rotary evaporation. The resulting residue was purified by chromatography (silica) using 5% ethyl acetate/hexane as eluent to give compound II (428 mg,3.4mmol,85% yield) as a brown crystalline solid.
Second step
To a stirred solution of compound II (428 mg,3.4 mmol) in acetone (17 ml, 0.2M) was added anhydrous potassium carbonate (1.4 g,10.2mmol,3.0 eq). After stirring at ambient temperature for 10min, dimethyl sulfate (0.81 ml,8.5mmol,2.5 eq.) was added and the reaction mixture was stirred at ambient temperature for 5 hours. The reaction was quenched with deionized water (50 mL) and the acetone was removed by rotary evaporation. Ethyl acetate (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with additional ethyl acetate (2X 20 mL). The combined organic layers were washed with water and brine, dried (sodium sulfate) and concentrated by rotary evaporation. The residue was purified by column chromatography (silica) using hexane/ethyl acetate (9:1) as eluent to give compound III (758 mg,3.13mmol, 92%) as a white solid.
Third step
Compound III (758 mg,3.13 mmol), azobisisobutyronitrile (26 mg,0.16 mmol) and N-bromosuccinimide (1.11 g,6.26mmol, crystallized from water) were dissolved in carbon tetrachloride (15 mL). The reaction mixture was heated to 85 ℃ and stirred under argon for 2h. The solution was filtered and the solvent was removed by rotary evaporation. The residue was purified by column chromatography (silica) using 5% ethyl acetate/hexane as eluent to give compound IV (720 mg,1.8mmol,57% yield) as a yellow solid.
Fourth step
To a solution of CuI (284 mg,1.5 mmol) and Compound IV (1.2 g,3.0 mmol) in dry THF (15 ml) was slowly added a solution of vinylmagnesium bromide (12 ml,1.0M in THF) at 3ml/min using a syringe pump at-78℃under argon. The resulting mixture was warmed to ambient temperature and stirred for 8h. The reaction was then quenched by addition of 15ml of saturated NH 4 Cl solution. The mixture was extracted with diethyl ether (15 mL. Times.2). The combined organic layers were dried over anhydrous Na 2SO4 and filtered. After removal of the solvent by rotary evaporation, the residue was purified by column chromatography (silica) using 5% ethyl acetate/hexane as eluent to give compound V (668mg, 2.25mmol,75% yield) as a clear oil.
Fifth step
To a solution of compound V (50 mg,0.17 mmol) in distilled dichloromethane (1 ml) was added a solution of BBr 3 (0.4 ml,1m in dichloromethane) at-40 ℃ under argon. The resulting mixture was warmed to ambient temperature and stirred for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3X 10 ml). The combined organic layers were washed with brine (10 ml), dried over Na 2SO4, and filtered. The solvent was concentrated by rotary evaporation and the residue was purified by column chromatography (silica) using 20% ethyl acetate/hexane as eluent to give honokiol (32 mg,0.12mmol,73% yield) as a white solid.
The effects of example 1 compared with those of comparative example 1 are shown in Table 1.
Table 1 comparison of effects of example 1 and comparative example 1
Comparative example 2
Reference KENICHI HARADA et al, publication EFFICIENT SYNTHESIS of neurotrophic honokiol using Suzuki-Miyaura Reactions, describes the following synthetic route:
The first step:
To 2-bromophenol (5.0 g,28.9 mmol) and 4-hydroxyphenylboronic acid (8.0 g, 58.0 mmol) were added THF (300 ml), followed by Pd (OAc) 2 (1.3 g,5.79 mmol), DPPF (3.2 g,5.79 mmol) and K 2CO3 (24.0 g,173.65 mmol), stirred at room temperature and vacuum displaced. Then after stirring at 70℃for 1.5 hours at elevated temperature, the reaction mixture was filtered through celite, washed with acetone, concentrated in vacuo, and the residue was purified by column chromatography over silica gel eluting with n-hexane/ethyl acetate (3:1 to 1:1) to give compound 4 (4.1 g, 76.2%).
And a second step of:
To compound 4 (4.1 g,22.02 mmol) was added CS 2 (225 ml) to dissolve, bromine (8.0 g,50.36 mmol) was added at 0 ℃, the reaction was stirred at 0 ℃ for 14 hours, quenched with saturated Na 2SO3 solution then extracted with dichloromethane, washed with brine, dried over Na 2SO4, and concentrated in vacuo. The crude mixture (8.2 g) was dissolved in pyridine (225 ml) and Ac 2 O (11.8 g,115.60 mmol) was added to the solution. After stirring at room temperature for 10 hours, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography over silica gel using toluene/ethyl acetate (13:1) to give diacetate 3 (5.9 g, 62.6% overall yield of the two steps).
And a third step of:
To diacetate 3 (5.9 g,13.79 mmol) was added allylboronic acid pinacol ester (13.9 g,82.9 mmol) and CsF (8.3 g,55.0 mmol), THF (380 ml) and Pd (PPh 3）4 (3.2 g,2.77 mmol) were added the reaction was stirred at 70℃for 16h, the mixture was filtered through celite and concentrated in vacuo, the residue (23 g) was dissolved in THF (1900 ml), liAlH 4 (21.0 g,553.86 mmol) was added to the reaction mixture at 0℃and stirred at 0℃for 14 h, the reaction mixture was quenched with water, then extracted with ethyl acetate, washed with brine, dried with Na 2SO4 and concentrated in vacuo, the residue was purified by column chromatography over silica gel eluting with n-hexane/ethyl acetate (4:1) to give honokiol (1.9 g, two steps total yield 51.8%).
The effect comparison of example 1 with comparative example 2 is shown in table 2.
Table 2 comparison of effects of example 1 and comparative example 2
It should be noted that the above examples are only for further illustrating and describing the technical solution of the present invention, and are not intended to limit the technical solution of the present invention, and the method of the present invention is only a preferred embodiment and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (9)

1. A process for the preparation of a compound of formula I,
The method is characterized by comprising the following steps:
(1) The compound SM1 and the compound SM2 are subjected to coupling reaction in the presence of a catalyst and oxygen atmosphere to prepare an intermediate 1,
；
(2) Intermediate 1 is subjected to tert-butyl removal under acidic conditions to prepare a compound of formula I.
2. The method of claim 1, wherein the catalyst in step (1) is Cr-Salen-Cy; the molar ratio of compound SM1 to compound SM2 is 1:1.0 to 1.5; the molar ratio of the compound SM1 to the catalyst is 1:0.020 to 0.030.
3. The method according to claim 1, wherein the solvent for the coupling reaction in the step (1) is one or more selected from toluene, N-dimethylformamide, and 1, 4-dioxane; the coupling reaction temperature is 60-110 ℃, and the coupling reaction time is 10-16 h.
4. The method of claim 1, wherein the acidic condition in step (2) is the use of methanesulfonic acid; the molar ratio of intermediate 1to methanesulfonic acid is 1: 8-12.
5. The method according to claim 1, wherein the solvent from which the tert-butyl group is removed in the step (2) is one or more selected from toluene, N-dimethylformamide, and 1, 4-dioxane; the temperature for removing the tertiary butyl is 20-60 ℃ and the time is 7-8 hours.
6. The preparation method of honokiol is characterized by comprising the following steps:
(a) Reacting a compound of formula I, a base and butyl chloroformate to obtain an intermediate 2, wherein the compound of formula I is prepared by the method of claims 1-5,
；
(B) Reacting the intermediate 2 with allyl tributylstannane in the presence of a catalyst to obtain an intermediate 3,
；
(C) Intermediate 3 decarbonizes butyl ester under alkaline condition to obtain honokiol.
7. The process according to claim 6, wherein the alkali in the step (a) is one or more selected from the group consisting of potassium carbonate, sodium carbonate and sodium hydroxide; the molar ratio of the compound of formula I, the base and the butyl chloroformate is 1:2.5 to 3.5: 2-3; the solvent for the reaction is selected from one or more than two of tetrahydrofuran, N-dimethylformamide and 1, 4-dioxane; the reaction temperature is 50-60 ℃ and the reaction time is 6-7 h.
8. The method of claim 6, wherein the catalyst in step (b) is bis (triphenylphosphine) palladium dichloride; intermediate 2, catalyst and allyl tributylstannane molar ratio 1: 0.02-0.08: 2.0-2.5; the reaction solvent is selected from 1, 4-dioxane and/or N, N-dimethylformamide; the reaction temperature is 60-100 ℃ and the reaction time is 1-2 h.
9. The process according to claim 6, wherein the alkali in step (c) is sodium hydroxide and/or potassium hydroxide; the solvent for removing butyl carbonate is one or more than two of ethanol, tetrahydrofuran and acetonitrile; the temperature of the butyl decarbonized acid is 0-30 ℃ and the time is 3-5 h.
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