CN115160120A - Method for synthesizing polyalkoxy aromatic ketone - Google Patents
Method for synthesizing polyalkoxy aromatic ketone Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/0827—Syntheses with formation of a Si-C bond
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/0832—Other preparations
Abstract
The invention provides a method for synthesizing polyalkoxy aromatic ketone. The synthesis method comprises the following steps: step S1, under nitrogen or inert atmosphere, taking polyalkoxy-substituted aromatic hydrocarbon as a raw material, and introducing trimethylsilyl into the ortho position of the polyalkoxy-substituted aromatic hydrocarbon by utilizing trimethylchlorosilane to obtain a first intermediate compound; s2, taking the first intermediate compound as a raw material to perform a halogenation reaction to obtain a second intermediate compound; s3, in the atmosphere of nitrogen or inert gas, a second intermediate compound is taken as a raw material to carry out acetylation reaction to obtain polyalkoxy aromatic ketone; the polyalkoxy-substituted aromatic hydrocarbon has the general formulaThe first intermediate compound has the formulaSecond intermediateThe compound has the general formulaThe general formula of the polyalkoxy aromatic ketone isWherein R is selected from C 1 ~C 5 Alkyl of (C) 1 ~C 5 An alkylene group of (a). The method can solve the problem of poor position selectivity of Friedel-crafts acylation reaction, and efficiently synthesize the ortho-acetylated polyalkoxy aromatic ketone.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing polyalkoxy aromatic ketone.
Background
The poly alkoxy aromatic ketone is a structural unit commonly existing in antitumor drugs, nervous system drugs and anti-inflammatory drugs. 4-bromo-2,3-dimethoxyacetophenone belongs to a polyalkoxy aromatic ketone derivative, is a key intermediate for drug synthesis, can be used for synthesis of various related medical products and natural products, and for example, an analogue (the structure is shown as formula I) of the derivative is used for chemical synthesis of a Rho kinase inhibitor 5-benzyl isoquinoline derivative for treating cardiovascular diseases.
The preparation of 4-bromo-2,3-dimethoxyacetophenone relates to a main technology of ketone carbonyl construction, and most of the prior methods adopt Friedel-crafts acylation reaction under acidic conditions to introduce carbonyl. For the substrate of the polyalkoxy substituted aromatic hydrocarbon, the method generally has the problems of poor position selectivity, low yield and difficult separation and purification.
Disclosure of Invention
The invention mainly aims to provide a method for synthesizing polyalkoxy aromatic ketone, which solves the problem of poor selectivity of the method for synthesizing polyalkoxy aromatic ketone by Friedel-crafts acylation reaction in the prior art.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a method for synthesizing a polyalkoxy aromatic ketone, the method comprising: step S1, under nitrogen or inert atmosphere, taking polyalkoxy-substituted aromatic hydrocarbon as a raw material, and introducing trimethylsilyl into the ortho position of the polyalkoxy-substituted aromatic hydrocarbon by utilizing trimethylchlorosilane to obtain a first intermediate compound; s2, taking the first intermediate compound as a raw material to perform a halogenation reaction to obtain a second intermediate compound; s3, in the atmosphere of nitrogen or inert gas, a second intermediate compound is taken as a raw material to carry out acetylation reaction to obtain polyalkoxy aromatic ketone; polyalkoxy-substituted aromatic hydrocarbons of the general formulaThe first intermediate compound has the formulaThe second intermediate compound has the formulaThe general formula of the poly alkoxy aromatic ketone isWherein R is selected from C 1 ~C 5 Alkyl of (C) 1 ~C 5 An alkylene group of (2).
Further, R is one or more of methyl, ethyl, n-propyl, n-butyl, n-pentyl and ethylene; preferably, R is methyl.
Further, step S1 includes: mixing polyalkoxy-substituted aromatic hydrocarbon, trimethylchlorosilane, a complexing agent, a first organic solvent and n-hexane solution of n-butyllithium at 0-5 ℃ in nitrogen or inert atmosphere to obtain a first mixed solution, and dispersing the first mixed solution at room temperature to obtain a first intermediate compound.
Further, the molar ratio of the polyalkoxy substituted aromatic hydrocarbon to the trimethylchlorosilane to the complexing agent is 1.0-1.5; preferably, the complexing agent is tetramethylethylenediamine; preferably, the concentration of n-hexane solution of n-butyllithium is 1-4M, and the dispersion time is 1-2 h; preferably, the first organic solvent is diethyl ether and/or tetrahydrofuran.
Further, step S2 includes: mixing the first intermediate compound, the second organic solvent and n-hexane solution of n-butyllithium at the temperature of 0-5 ℃ to obtain a second mixed solution, and preferably stirring the second mixed solution at room temperature for 1-2 h; cooling the second mixed solution to-60 to-70 ℃, adding a halogen simple substance, and carrying out a halogenation reaction to obtain a second intermediate compound; preferably, the concentration of n-hexane solution of n-butyllithium is 1-4M; preferably, the second organic solvent is diethyl ether and/or tetrahydrofuran.
Further, the molar ratio of the simple halogen to the first intermediate compound is 1.1-1.6: 1; preferably, the halogen elementary substance is liquid bromine and/or elementary substance iodine; the temperature of the halogenation reaction is preferably-30 to-50 ℃.
Further, step S3 includes: mixing a third organic solvent, lewis acid and an acylating reagent at the temperature of 0-5 ℃ in nitrogen or inert atmosphere to obtain a third mixed solution; and cooling the third mixed solution to-20 to-30 ℃, adding a dichloromethane solution of the second intermediate compound, and carrying out acetylation reaction to obtain the poly-alkoxy aromatic ketone.
Further, the third organic solvent is 1,2-dichloroethane, and the time of acetylation reaction is preferably 2 to 3 hours.
Further, the molar ratio of the Lewis acid to the acylating agent is 1.1-1.3; preferably, the concentration of the dichloromethane solution of the second intermediate compound is 0.2-1.0M; preferably the lewis acid is aluminium chloride and preferably the acylating agent is acetyl chloride.
Further, the synthesis method also comprises a preparation method of the polyalkoxy substituted aromatic hydrocarbon: mixing a phenolic aromatic compound, RX, a fourth organic solvent and a basic substance under nitrogen or inert atmosphere to obtain the aromatic hydrocarbon substituted by the polyalkoxy; preferably, the phenolic aromatic compound is catechol, preferably RX is one or more of methyl iodide, ethyl bromide, propyl bromide, butyl bromide, pentyl bromide, 1,2-dibromoethane; preferably, the fourth organic solvent is one or more of DMF, acetone and acetonitrile; preferably, the alkaline substance is one or more of potassium carbonate, sodium carbonate and sodium hydroxide.
By applying the technical scheme of the invention, the trimethylsilyl is introduced at the ortho position of the polyalkoxy substituted aromatic hydrocarbon, then acetylation reaction is carried out to replace the trimethylsilyl, and the trimethylsilyl is converted into the ketocarbonyl in situ by utilizing the positioning effect of the trimethylsilyl to reduce the generation of isomers, thereby simplifying the separation, effectively solving the problem of poor position selectivity of the Friedel-crafts acylation reaction in the prior art, and efficiently synthesizing the ortho-acetylated polyalkoxy aromatic ketone. The synthesis method has the advantages of mild conditions, no high temperature and high pressure, low energy consumption, safety and reliability.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As analyzed in the background art, the method of synthesizing polyalkoxyaromatic ketones by Friedel-crafts acylation in the prior art has a problem of poor position selectivity, and at the same time, friedel-crafts acylation generates positional isomers, which have a problem of difficulty in separating isomers because the isomers have the same or similar polarity to the product. In order to solve the problems, the application provides a method for synthesizing polyalkoxy aromatic ketone.
In an exemplary embodiment of the present application, there is provided a method for synthesizing polyalkoxy aromatic ketone, comprising: step S1, under nitrogen or inert atmosphere, taking polyalkoxy-substituted aromatic hydrocarbon as raw material, introducing trimethylsilyl group at ortho position of the polyalkoxy-substituted aromatic hydrocarbon by utilizing trimethylchlorosilane to obtain first intermediateA compound; s2, taking the first intermediate compound as a raw material to perform a halogenation reaction to obtain a second intermediate compound; and S3, performing acetylation reaction by taking the second intermediate compound as a raw material under the nitrogen or inert atmosphere to obtain the polyalkoxy aromatic ketone. The polyalkoxy-substituted aromatic hydrocarbon has the general formulaThe first intermediate compound has the formulaThe second intermediate compound has the formulaThe general formula of the polyalkoxy aromatic ketone isWherein R is selected from C 1 ~C 5 Alkyl of (C) 1 ~C 5 An alkylene group of (a).
According to the method, trimethylsilyl is introduced into ortho positions of the polyalkoxy substituted aromatic hydrocarbon, acetylation is carried out to replace trimethylsilyl, and the trimethylsilyl is converted into ketone carbonyl in situ by utilizing the positioning effect of the trimethylsilyl to reduce the generation of isomers, so that the separation is simplified, the problem of poor position selectivity of Friedel-crafts acylation in the prior art is effectively solved, and the ortho-acetylated polyalkoxy aromatic ketone is efficiently synthesized. The synthesis method has the advantages of mild conditions, no high temperature and high pressure, low energy consumption, safety and reliability.
The synthetic method has good substrate applicability, is suitable for preparing a plurality of polyalkoxy aromatic ketones, and in some embodiments, R is one or more of methyl, ethyl, n-propyl, n-butyl, n-pentyl and ethylene; more preferably, R is methyl. The synthetic route provided by the invention is more suitable for synthesizing 4-bromo-2,3-dimethoxyacetophenone, and due to the particularity of the substrate, the preparation processes of the first intermediate compound and the second intermediate compound can achieve higher selectivity and higher yield, and the reaction process conditions are milder and controllable.
In some embodiments, step S1 comprises: mixing polyalkoxy-substituted aromatic hydrocarbon, trimethylchlorosilane, a complexing agent, a first organic solvent and n-BuLi n-hexane solution at 0-5 ℃ (such as 0 ℃,1 ℃,2 ℃,3 ℃, 4 ℃ and 5 ℃) in a nitrogen or inert atmosphere to obtain a first mixed solution, and dispersing the first mixed solution at room temperature (20-30 ℃) to obtain a first intermediate compound. The method is carried out under the temperature condition and in the reaction system, the reaction process is more stable and efficient, and the selectivity and the yield of the target intermediate product are higher.
In order to control the introduction of trimethylsilyl groups in the ortho-position of the polyalkoxy-substituted aromatic hydrocarbon and avoid introducing trimethylsilyl groups in other positions, the molar ratio of polyalkoxy-substituted aromatic hydrocarbon to trimethylchlorosilane to a complexing agent is controlled to be 1.0-1.5, and the molar ratio of polyalkoxy-substituted aromatic hydrocarbon to trimethylchlorosilane to the complexing agent is controlled to be 1.3; preferably, the catalyst is tetramethylethylenediamine; preferably the concentration of n-BuLi in n-hexane solution is 1-4M, for example the concentration of n-BuLi in n-hexane solution is 2.5M, and the preferable dispersion time is 1-2 h; preferably, the first organic solvent is diethyl ether and/or tetrahydrofuran.
The halogenation step in the present application may refer to the steps commonly used in the art. In some embodiments, step S2 comprises: mixing the first intermediate compound, the second organic solvent, and the n-hexane solution of n-BuLi at a temperature of 0 ℃ to 5 ℃ (e.g., 0 ℃,1 ℃,2 ℃,3 ℃, 4 ℃, 5 ℃) to obtain a second mixed solution, and preferably stirring the second mixed solution at room temperature for 1 to 2 hours; cooling the second mixed solution to-60 to-70 ℃ (such as-60 ℃, 65 ℃ and 70 ℃), adding a halogen simple substance, and carrying out a halogenation reaction to obtain a second intermediate compound; preferably, the n-hexane solution of n-BuLi has a concentration of 1 to 4M (e.g., 2.5M); preferably, the second organic solvent is diethyl ether and/or tetrahydrofuran. Through the positioning effect of the methoxyl, the halogenation reaction is promoted to occur at the para position of the silicon base. Meanwhile, the product is ensured to exist stably under the condition that excessive bromine exists through lower reaction temperature, and side reactions are reduced as far as possible. The reaction temperature of the method is important, the second mixed solution is obtained at room temperature, the hydrogen can be completely grabbed, the halogen simple substance is added under the low-temperature condition, the halogenation reaction is carried out, and the stable existence of the product can be ensured.
To further improve the efficiency of the halogenation reaction and avoid the insufficient halogenation reaction, in some embodiments, the molar ratio of the elemental halogen and the first intermediate compound is 1.1 to 1.6, for example the molar ratio of the elemental halogen and the first intermediate compound is 1.5; preferably, the halogen elementary substance is liquid bromine and/or elementary substance iodine; preferably, the temperature of the halogenation reaction is from-30 ℃ to-50 ℃ (e.g., -30 ℃, -35 ℃, -40 ℃, -45 ℃, -50 ℃). Too high a molar ratio of the simple halogen to the first intermediate compound leads to silicon group exfoliation in the product, and too low leads to incomplete halogenation.
The acetylation reaction conditions in the present application may refer to those commonly used in the art. To increase the efficiency of the acetylation reaction, in some embodiments, step S3 comprises: mixing the third organic solvent, the Lewis acid and the acylating agent in nitrogen or inert atmosphere at 0-5 deg.C (such as 0 deg.C, 1 deg.C, 2 deg.C, 3 deg.C, 4 deg.C, 5 deg.C) to obtain a third mixed solution; cooling the third mixed solution to-20 to-30 ℃ (such as-20 to-25 to-30 ℃), adding a dichloromethane solution of the second intermediate compound, and carrying out acetylation reaction to obtain polyalkoxy aromatic ketone; preferably, the third organic solvent is 1,2-dichloroethane, and the acetylation reaction time is preferably 2 to 3 hours. The acetylation reaction condition of the application is mild, and the product yield obtained by acetylation reaction under the condition is also high.
To further increase the efficiency of the acetylation reaction and avoid side reactions, in some embodiments, the molar ratio of lewis acid to acylating agent is 1.1 to 1.3; preferably, the concentration of the dichloromethane solution of the second intermediate compound is 0.2 to 1M.
The type of lewis acid and acylating agent is not particularly limited herein, and in some embodiments, the lewis acid is preferably aluminum chloride, and the acylating agent is preferably acetyl chloride. In the present application, the polyalkoxy-substituted aromatic hydrocarbons can be synthesized by methods known in the art. In some embodiments, the synthesis methods further include methods of preparing polyalkoxy-substituted aromatic hydrocarbons: mixing a phenolic aromatic compound, RX, a fourth organic solvent and a basic substance in a nitrogen or inert atmosphere to obtain polyalkoxy substituted aromatic hydrocarbon; preferably, the phenolic aromatic compound is catechol, preferably RX is one or more of methyl iodide, ethyl bromide, propyl bromide, butyl bromide, pentyl bromide, 1,2-dibromoethane; preferably, the fourth organic solvent is one or more of DMF, acetone and acetonitrile; preferably, the alkaline substance is one or more of potassium carbonate, sodium carbonate and sodium hydroxide.
The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.
Example 1
The reaction equation is as follows:
the first step is as follows: preparation of o-dimethyl ether
Under the protection of nitrogen, catechol (10g, 1.0eq) and DMF (100 mL) are added into a 250mL three-necked bottle and stirred to be dissolved to obtain a dark yellow clear solution, the solution is cooled by an ice bath, and potassium carbonate (31.0 g, 2.5eq) is slowly added to change the yellow color of the solution into dark gray color. After the completion of the addition, stirring was carried out for 20min, and methyl iodide (38.4g, 3.0eq) was added dropwise. After the dropwise addition, removing the ice water, and recovering to 20-25 ℃ for overnight reaction.
The system was poured into 500mL of water, extracted with ethyl acetate, the organic phases combined and washed with water to remove DMF. Dried over anhydrous sodium sulfate, filtered and concentrated to give 11g of a light brown liquid, yield 93.7%.
GCMS 138.05(M)
1 H NMR(400MHz,DMSO-d6)δ6.98-6.94(m,1H),6.93(d,J=3.8Hz,1H),6.90(d,J=3.8Hz,1H),6.89-6.85(m,1H),3.74(s,6H)。
The second step is that: preparation of 3-trimethyl silicon-o-dimethyl ether
To a 1000mL three-necked flask were added o-dimethyl ether (20g, 1.0eq) and diethyl ether (200 mL) under nitrogen protection. TMEDA (22.0 g,1.3 eq) was added under cooling with ice water, then n-BuLi Hexane solution (2.5M, 75.4mL,1.3 eq) was added dropwise, and the mixture was stirred for 1 hour after the temperature was raised to 20 to 25 ℃. Under the cooling of ice water, trimethylchlorosilane (20.5g, 1.3eq) is added dropwise and stirred for 30min at the temperature of 0-5 ℃. The temperature is increased to 20-25 ℃, the mixture is stirred for 1h, and the reaction is monitored by TLC.
Slowly pouring the system into saturated sodium bicarbonate water solution, extracting by ethyl acetate, combining organic phases, washing by saturated sodium chloride, drying by anhydrous sodium sulfate, filtering and concentrating to obtain brown liquid 29.6g with the yield of 96.5%.
GCMS 176.20(M)
1 H NMR(400MHz,DMSO-d 6 )δ7.11-6.99(m,2H),6.90-6.85(m,1H),3.79(s,3H),3.75(s,3H),0.23(s,9H)。
The third step: preparation of 1-bromo-4-trimethylsilyl-o-dimethylether
To a 50mL three-necked flask were added 3-trimethylsilane-o-dimethylether (1g, 1.0 eq) and ether (10 mL). While the mixture was cooled with ice water, a solution of 2.5M n-BuLi in Hexane (2.9 mL,1.5 eq) was added dropwise thereto, and the mixture was allowed to warm to room temperature and stirred for 1 hour. The temperature was reduced to-70 ℃ and liquid bromine (1.15g, 1.5eq) was added dropwise. After the addition, the temperature was raised to-40 ℃ and the mixture was stirred, and the completion of the reaction was monitored by TLC.
Pouring the system into saturated sodium bisulfite aqueous solution, extracting with ethyl acetate, combining organic phases, washing with saturated NaCl aqueous solution, drying with anhydrous sodium sulfate, and removing the solvent by rotary evaporation to obtain crude product 1.0g of light red liquid. Purifying by column chromatography to obtain colorless liquid 650mg. The yield was 56.8%, mainly due to the residue of starting material.
GCMS(M)288.10,290.10
1 H NMR(400MHz,DMSO-d 6 )δ7.34(d,J=7.9Hz,1H),7.00(d,J=7.9Hz,1H),3.84(s,3H),3.77(s,3H),0.25(s,9H)。
The fourth step: preparation of 4-bromo-2,3-dimethoxyacetophenone
Under nitrogen protection, 1,2-dichloroethane (10 mL) was added to a 50mL three-necked flask, and aluminum chloride (560mg, 1.2eq) and acetyl chloride (360mg, 1.3eq) were added in this order with ice water cooling. The temperature is reduced to-20 ℃,1,2-dichloroethane solution (1.0 g,1.0eq,10mL 1, 2-dichloroethane) of 1-bromo-4-trimethylsilane-o-dimethylether is added dropwise, stirring is carried out for 2h, and TLC shows that the raw materials are completely reacted.
And pouring the system into sodium carbonate aqueous solution, adding dichloromethane for separating liquid, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and removing the solvent by rotary removal to obtain 1g of crude product. Performing column chromatography to obtain colorless liquid 400mg. The yield is 44.8%, mainly because some silicon-based stripping by-products are generated in the reaction, and a small amount of acetyl is formed at other positions to form by-products.
GC-MS:258.1,260.10
1 H NMR(400MHz,DMSO-d6)δ7.46(d,J=8.5Hz,1H),7.30(d,J=8.5Hz,1H),3.91(s,3H),3.82(s,3H),2.56(s,3H)。
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects: introducing trimethylsilyl group at the ortho position of the polyalkoxy substituted aromatic hydrocarbon, performing acetylation reaction to replace trimethylsilyl group, and converting trimethylsilyl group into ketone carbonyl in situ by using the positioning effect of trimethylsilyl group to reduce the generation of isomers, thereby simplifying the separation, effectively solving the problem of poor position selectivity of Friedel-crafts acylation reaction in the prior art, and efficiently synthesizing the ortho-acetylated polyalkoxy aromatic ketone. The synthesis method has the advantages of mild conditions, no high temperature and high pressure, low energy consumption, safety and reliability.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for synthesizing polyalkoxy aromatic ketone is characterized in that the method comprises the following steps:
step S1, under nitrogen or inert atmosphere, taking polyalkoxy-substituted aromatic hydrocarbon as a raw material, and introducing trimethylsilyl into the ortho position of the polyalkoxy-substituted aromatic hydrocarbon by utilizing trimethylchlorosilane to obtain a first intermediate compound;
s2, taking the first intermediate compound as a raw material to carry out halogenation reaction to obtain a second intermediate compound;
s3, performing acetylation reaction on the second intermediate compound serving as a raw material in a nitrogen or inert atmosphere to obtain the polyalkoxy aromatic ketone;
the general formula of the polyalkoxy-substituted aromatic hydrocarbon isThe first intermediate compound has the general formulaThe second intermediate compound has the formulaThe general formula of the polyalkoxy aromatic ketone isWherein R is selected from C 1 ~C 5 Alkyl of (C) 1 ~C 5 An alkylene group of (a).
2. The synthesis method of claim 1, wherein R is one or more of methyl, ethyl, n-propyl, n-butyl, n-pentyl and ethylene; preferably, R is methyl.
3. The synthesis method according to claim 1, wherein the step S1 comprises:
mixing polyalkoxy-substituted aromatic hydrocarbon, trimethylchlorosilane, a complexing agent, a first organic solvent and n-hexane solution of n-butyllithium at 0-5 ℃ in nitrogen or inert atmosphere to obtain a first mixed solution,
and dispersing the first mixed solution at room temperature to obtain the first intermediate compound.
4. The synthesis method according to claim 3, wherein the molar ratio of the polyalkoxy-substituted aromatic hydrocarbon to the trimethylchlorosilane to the complexing agent is 1.0 to 1.5; preferably, the complexing agent is tetramethylethylenediamine; preferably, the concentration of the n-hexane solution of the n-butyllithium is 1-4M, and the dispersing time is 1-2 h; preferably, the first organic solvent is diethyl ether and/or tetrahydrofuran.
5. The synthesis method according to claim 1, wherein the step S2 comprises:
mixing the first intermediate compound, a second organic solvent and an n-hexane solution of n-butyllithium at a temperature of 0-5 ℃ to obtain a second mixed solution, and preferably stirring the second mixed solution at room temperature for 1-2 hours;
cooling the second mixed solution to-60 to-70 ℃, adding a halogen simple substance and carrying out a halogenation reaction to obtain a second intermediate compound;
preferably, the concentration of the n-hexane solution of the n-butyllithium is 1-4M;
preferably, the second organic solvent is diethyl ether and/or tetrahydrofuran.
6. The method according to claim 5, wherein the molar ratio of the simple halogen to the first intermediate compound is 1.1 to 1.6:1; preferably, the elementary halogen is liquid bromine and/or elementary iodine;
the temperature of the halogenation reaction is preferably-30 to-50 ℃.
7. The synthesis method according to claim 1, characterized in that said step S3 comprises:
mixing a third organic solvent, lewis acid and an acylating reagent in nitrogen or inert atmosphere at the temperature of 0-5 ℃ to obtain a third mixed solution;
and cooling the third mixed solution to-20 to-30 ℃, adding a dichloromethane solution of the second intermediate compound, and carrying out acetylation reaction to obtain the poly-alkoxy aromatic ketone.
8. The synthesis method according to claim 7, wherein the third organic solvent is 1,2-dichloroethane, and the acetylation reaction time is preferably 2 to 3 hours.
9. The synthesis method according to claim 7 or 8, wherein the molar ratio of the Lewis acid to the acylating agent is 1.1-1.3; preferably, the concentration of the dichloromethane solution of the second intermediate compound is 0.2-1.0M; preferably the lewis acid is aluminium chloride and preferably the acylating agent is acetyl chloride.
10. The synthesis process according to any one of claims 1 to 9, characterized in that it further comprises a preparation process of polyalkoxy-substituted aromatic hydrocarbons:
mixing a phenolic aromatic compound, RX, a fourth organic solvent and a basic substance under nitrogen or inert atmosphere to obtain the polyalkoxy-substituted aromatic hydrocarbon;
preferably the phenolic aromatic compound is catechol,
preferably, RX is one or more of methyl iodide, ethyl bromide, propyl bromide, butyl bromide, pentyl bromide, 1,2-dibromoethane;
preferably, the fourth organic solvent is one or more of DMF, acetone and acetonitrile;
preferably, the alkaline substance is one or more of potassium carbonate, sodium carbonate and sodium hydroxide.
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