[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN107118088A - A kind of preparation method of m-hydroxy acetophenone - Google Patents

A kind of preparation method of m-hydroxy acetophenone Download PDF

Info

Publication number
CN107118088A
CN107118088A CN201710451177.7A CN201710451177A CN107118088A CN 107118088 A CN107118088 A CN 107118088A CN 201710451177 A CN201710451177 A CN 201710451177A CN 107118088 A CN107118088 A CN 107118088A
Authority
CN
China
Prior art keywords
acid
chloride
acetylation
preparation
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201710451177.7A
Other languages
Chinese (zh)
Inventor
邓晋
徐海
汪鹏
杨平
李磊
姜娜
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HEFEI LIFU BIO-TECH Co Ltd
Original Assignee
HEFEI LIFU BIO-TECH Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by HEFEI LIFU BIO-TECH Co Ltd filed Critical HEFEI LIFU BIO-TECH Co Ltd
Priority to CN201710451177.7A priority Critical patent/CN107118088A/en
Publication of CN107118088A publication Critical patent/CN107118088A/en
Pending legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C07C45/676Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton by elimination of carboxyl groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/373Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58Preparation of carboxylic acid halides
    • C07C51/60Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00Preparation of carboxylic acid esters
    • C07C67/30Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/313Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a kind of preparation method of m-hydroxy acetophenone, comprise the following steps:M-hydroxybenzoic acid acetylation is obtained into an acetoxy-benzoic acid, then chloride obtains an acetoxyl group chlorobenzoyl chloride, then obtains 3 acetyloxy phenyl formylmaloic acid diethylesters with the reaction of diethyl malonate sodium salt solution, last decarboxylation obtains m-hydroxy acetophenone.The present invention is simple to operate, and raw material is cheap and easily-available, and synthesis is easy, and side reaction is few, with higher yield.

Description

A kind of preparation method of m-hydroxy acetophenone
Technical field
The present invention relates to chemical substance preparing technical field, more particularly to a kind of preparation method of m-hydroxy acetophenone.
Background technology
Phyenlephrinium (Phenylephrine) is a kind of new drug, is a kind of vasoactive drug of Hemorrhagic shock, for infecting Poisoning and anaphylactic shock, supraventricular tachycardia, low blood pressure, mydriasis inspection when preventing and treating general anesthesia and lumbar anesthesia, it is tied Structure formula is as follows:
Wherein, m-hydroxy acetophenone is its crucial synthesis fragment intermediate.At present it is known that m-hydroxy acetophenone synthesis Method has:The synthetic route of Hangzhou literature of the chemical engineering report, its synthetic route is as follows:
Using acetophenone as raw material, m-hydroxy acetophenone has been synthesized by a nitrated in position, reduction and diazotising hydrolysis.This The yield of route is relatively low, and total recovery is only about 42.3%, and each step of this route is both needed to using a large amount of difficult recovered solvents, Environmental pollution is larger, and the purity of the m-hydroxy acetophenone prepared is relatively low.
The content of the invention
The technical problem existed based on background technology, the present invention proposes a kind of preparation method of m-hydroxy acetophenone, this Invention is simple to operate, and raw material is cheap and easily-available, and synthesis is easy, and side reaction is few, with higher yield.
A kind of preparation method of m-hydroxy acetophenone proposed by the present invention, comprises the following steps:By m-hydroxybenzoic acid second Acylation obtains an acetoxy-benzoic acid, then chloride obtains an acetoxyl group chlorobenzoyl chloride, then with diethyl malonate sodium Salting liquid reaction obtains 3- acetyloxy phenyl formylmaloic acid diethylesters, and last decarboxylation obtains m-hydroxy acetophenone.
Preferably, in acetylation, m-hydroxybenzoic acid carries out acetylization reaction with acetylation reagent, wherein, second Acylating reagent is acetic anhydride.
Preferably, the mol ratio of m-hydroxybenzoic acid and acetylation reagent is 1-1.5:1.
Preferably, in acetylation also need add acetylation catalyst, wherein, acetylation catalyst be sodium acetate, At least one of ammonium acetate, zinc acetate, lead acetate.
Preferably, the mol ratio of acetylation catalyst and m-hydroxybenzoic acid is 0.1-0.5:100.
Preferably, the reaction dissolvent of acetylation is in toluene, dichloromethane, ether, dichloroethanes, water, tetrahydrofuran It is at least one.
Preferably, the weight ratio of the reaction dissolvent of acetylation and m-hydroxybenzoic acid is 2-10:1.
Preferably, the temperature of acetylation is 30-100 DEG C, and the time is 2-4h.
Preferably, during chloride, an acetoxy-benzoic acid carries out acyl chloride reaction with chloride reagent, its In, chloride reagent is thionyl chloride.
Preferably, the mol ratio of an acetoxy-benzoic acid and chloride reagent is 1-2.5:1.
Preferably, also need to add chloride catalyst during chloride, wherein, chloride catalyst is N, N- diformazans Base formamide.
Preferably, the mol ratio of chloride catalyst and an acetoxy-benzoic acid is 1-5:100.
Preferably, the reaction dissolvent of chloride is toluene, ether, dichloromethane, dichloroethanes, water, tetrahydrofuran, ethanol At least one of.
Preferably, the reaction dissolvent of chloride is high boiling solvent.
Preferably, the reaction dissolvent of chloride is ethanol or/and tetrahydrofuran.
Preferably, the temperature of chloride is 25-80 DEG C, and the time is 2-8h.
Preferably, in the preparation process of diethyl malonate sodium salt solution, diethyl malonate and alkaline matter containing sodium Reaction obtains diethyl malonate sodium salt solution in the first solvent.
Preferably, alkaline matter containing sodium is at least one of caustic alcohol, sodium methoxide, sodium hydroxide, sodium acid carbonate.
Preferably, the first solvent is at least one in toluene, dichloromethane, dichloroethanes, ether, tetrahydrofuran, ethanol Kind.
Preferably, the first solvent is tetrahydrofuran or/and ether.
Preferably, the mol ratio of diethyl malonate and the alkaline matter containing sodium is 1:1-5.
Preferably, the weight ratio of the first solvent and diethyl malonate is 1-10:1.
Preferably, the temperature of diethyl malonate and the alkali substance reaction containing sodium is 30-100 DEG C, and the time is 3-8h.
Preferably, in diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride course of reaction, malonic acid two Ethyl ester sodium salt solution and an acetoxyl group chlorobenzoyl chloride solution are reacted, wherein, an acetoxyl group chlorobenzoyl chloride solution it is molten Agent is the first solvent.
Preferably, the mass fraction of an acetoxyl group chlorobenzoyl chloride solution is 16.7-33.3wt%.
Preferably, volume weight (L/kg) ratio of diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride is 15:2.7-2.8.
Preferably, the temperature that diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride react is -10 to 0 DEG C, Time is 30min-2h.
Preferably, decarboxylation need to be carried out in sour environment.
Preferably, maintain sour environment with acidic materials, wherein, acidic materials be hydrochloric acid, sulfuric acid, acetic acid, to toluene At least one of sulfonic acid.
Preferably, the weight ratio of acidic materials and 3- acetyloxy phenyl formylmaloic acid diethylesters is 5-10:1.
Preferably, decarboxylation need to be carried out in acidic aqueous solution.
Preferably, the temperature of decarboxylation is 90-110 DEG C, and the time is 1-5h.
Preferably, the concrete operations of acetylation are:M-hydroxybenzoic acid is added in acetylization reaction solvent and dissolved, is added Acetylation reagent and acetylation catalyst, heat up, insulation, and cooling separates out solid, and filtering, drying obtains an acetyloxy phenyl first Acid.
Preferably, the concrete operations of chloride are:In nitrogen atmosphere, acetoxy-benzoic acid, acyl chloride reaction by between Solvent is mixed, and adds chloride catalyst, and chloride reagent is added dropwise, and is heated up, and insulation is concentrated to give an acetoxyl group benzoyl Chlorine.
Preferably, the concrete operations for preparing diethyl malonate sodium salt solution are:First solvent, diethyl malonate are mixed Even, stirring adds alkaline matter containing sodium, and heating, insulation obtains diethyl malonate sodium salt solution.
Preferably, the concrete operations for preparing 3- acetyloxy phenyl formylmaloic acid diethylesters are:Take diethyl malonate sodium Salting liquid, cooling, acetoxyl group chlorobenzoyl chloride solution between dropwise addition, insulation, then reaction is quenched in watery hydrochloric acid, and stratification has taken Machine is mutually spin-dried for obtaining 3- acetyloxy phenyl formylmaloic acid diethylesters.
Preferably, the concrete operations of decarboxylation are:3- acetyloxy phenyl formylmaloic acids diethylester is added into acidic aqueous solution It is middle to mix, backflow, cool crystallization, and centrifugation obtains m-hydroxy acetophenone.
The reaction dissolvent consumption of chloride is not provided during above-mentioned chloride, its consumption is determined according to concrete operations.
M-hydroxybenzoic acid of the present invention is raw material, cheap and easy to get, and reaction condition is gentle, and energy consumption is low, high income, prepares M-hydroxybenzoic acid purity it is good, it is environmentally friendly, it is simple to operate, be adapted to industrialized production.
Brief description of the drawings
Fig. 1 is a kind of synthetic route chart of the preparation method of m-hydroxy acetophenone proposed by the present invention.
Fig. 2 is the nuclear magnetic spectrum of acetoxy-benzoic acid between the present invention is prepared.
Fig. 3 is the gas phase collection of illustrative plates of acetoxy-benzoic acid between the present invention is prepared.
The nuclear magnetic spectrum for the m-hydroxy acetophenone that Fig. 4 prepares for the present invention.
Embodiment
As shown in figure 1, Fig. 1 is a kind of synthetic route chart of the preparation method of m-hydroxy acetophenone proposed by the present invention.
A kind of reference picture 1, preparation method of m-hydroxy acetophenone proposed by the present invention, comprises the following steps:The hydroxyl by between Benzoic acid acetylation obtains an acetoxy-benzoic acid, then chloride obtains an acetoxyl group chlorobenzoyl chloride, then with malonic acid The reaction of diethylester sodium salt solution obtains 3- acetyloxy phenyl formylmaloic acid diethylesters, and last decarboxylation obtains m-hydroxy acetophenone.
Below, technical scheme is described in detail by specific embodiment.
Embodiment 1
A kind of preparation method of m-hydroxy acetophenone, comprises the following steps:M-hydroxybenzoic acid is added to the water dissolving, plus Enter acetic anhydride and sodium acetate, be warming up to 80 DEG C, be incubated 2h, cooling separates out solid, and filtering, drying obtains an acetyloxy phenyl first Acid, wherein, the mol ratio of m-hydroxybenzoic acid and acetic anhydride is 1:1, the mol ratio of sodium acetate and m-hydroxybenzoic acid is 0.5: 100, the weight ratio of water and m-hydroxybenzoic acid is 10:1;
In nitrogen atmosphere, acetoxy-benzoic acid, ethanol are mixed by between, add DMF, are added dropwise two Chlorine sulfoxide, is warming up to 70 DEG C, is incubated 4h, is concentrated to give an acetoxyl group chlorobenzoyl chloride, wherein, an acetoxy-benzoic acid and two The mol ratio of chlorine sulfoxide is 1:1, the mol ratio of DMF and an acetoxy-benzoic acid is 1:100;
Toluene, diethyl malonate are mixed, stirring adds sodium hydroxide, are warming up to 80 DEG C, insulation 3h obtains malonic acid Diethylester sodium salt solution, wherein, the mol ratio of diethyl malonate and sodium hydroxide is 1:1, toluene and diethyl malonate Weight ratio is 5.9:1;
Diethyl malonate sodium salt solution is taken, -10 DEG C are cooled to, it is acetyloxy phenyl first between 20wt% that mass fraction, which is added dropwise, The toluene solution of acyl chlorides, is incubated 30min, and then reaction is quenched in watery hydrochloric acid, and stratification takes organic phase to be spin-dried for obtaining 3- acetyl oxygen Base benzoyl diethyl malonate, wherein, the volume weight of diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride (L/kg) than being 15:2.7;
3- acetyloxy phenyl formylmaloic acids diethylester is added mass fraction to mix in 10wt% aqueous hydrochloric acid solutions, risen Temperature is to 105 DEG C, and flow back 5h, is cooled to 10 DEG C of crystallizations, and centrifugation obtains m-hydroxy acetophenone, wherein, hydrochloric acid and 3- acetyloxy phenyls The weight ratio of formylmaloic acid diethylester is 5:1.
Embodiment 2
A kind of preparation method of m-hydroxy acetophenone, comprises the following steps:M-hydroxybenzoic acid is added in dichloroethanes Dissolving, adds acetic anhydride and ammonium acetate, is warming up to 80 DEG C, is incubated 2h, and cooling separates out solid, and filtering, drying obtains an acetyl oxygen Yl benzoic acid, wherein, the mol ratio of m-hydroxybenzoic acid and acetic anhydride is 1:1, the mol ratio of ammonium acetate and m-hydroxybenzoic acid For 0.5:100, the weight ratio of dichloroethanes and m-hydroxybenzoic acid is 8:1;
In nitrogen atmosphere, acetoxy-benzoic acid, dichloroethanes are mixed by between, add DMF, drop Plus thionyl chloride, 60 DEG C are warming up to, 5h is incubated, is concentrated to give an acetoxyl group chlorobenzoyl chloride, wherein, an acetoxy-benzoic acid Mol ratio with thionyl chloride is 1:1, the mol ratio of DMF and an acetoxy-benzoic acid is 5:100;
Ethanol, diethyl malonate are mixed, stirring adds caustic alcohol, are warming up to 75 DEG C, insulation 5h obtains malonic acid two Ethyl ester sodium salt solution, wherein, the mol ratio of diethyl malonate and caustic alcohol is 1:2.5, the weight of ethanol and diethyl malonate Amount is than being 5.4:1;
Diethyl malonate sodium salt solution is taken, -10 DEG C are cooled to, it is acetyloxy phenyl first between 20wt% that mass fraction, which is added dropwise, The ethanol solution of acyl chlorides, is incubated 30min, and then reaction is quenched in watery hydrochloric acid, and stratification takes organic phase to be spin-dried for obtaining 3- acetyl oxygen Base benzoyl diethyl malonate, wherein, the volume weight of diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride (L/kg) than being 15:2.8;
3- acetyloxy phenyl formylmaloic acids diethylester is added mass fraction to mix in 30wt% aqueous sulfuric acids, risen Temperature is to 110 DEG C, and flow back 5h, is cooled to 10 DEG C of crystallizations, and centrifugation obtains m-hydroxy acetophenone, wherein, sulfuric acid and 3- acetyloxy phenyls The weight ratio of formylmaloic acid diethylester is 5:1.
Embodiment 3
A kind of preparation method of m-hydroxy acetophenone, comprises the following steps:M-hydroxybenzoic acid is added in toluene and dissolved, Acetic anhydride and zinc acetate are added, 80 DEG C are warming up to, 2h is incubated, cooling separates out solid, and filtering, drying obtains an acetyloxy phenyl first Acid, wherein, the mol ratio of m-hydroxybenzoic acid and acetic anhydride is 1:1, the mol ratio of zinc acetate and m-hydroxybenzoic acid is 0.5: 100, the weight ratio of toluene and m-hydroxybenzoic acid is 6:1;
In nitrogen atmosphere, acetoxy-benzoic acid, dichloromethane are mixed by between, add DMF, drop Plus thionyl chloride, 35 DEG C are warming up to, 5h is incubated, is concentrated to give an acetoxyl group chlorobenzoyl chloride, wherein, wherein, an acetoxyl group The mol ratio of benzoic acid and thionyl chloride is 1:1, the mol ratio of DMF and an acetoxy-benzoic acid is 3: 100;
Tetrahydrofuran, diethyl malonate are mixed, stirring adds sodium acid carbonate, are warming up to 60 DEG C, insulation 5h obtains third Diethyl adipate sodium salt solution, wherein, the mol ratio of diethyl malonate and sodium acid carbonate is 1:2, tetrahydrofuran and malonic acid The weight ratio of diethylester is 6.1:1;
Diethyl malonate sodium salt solution is taken, -10 DEG C are cooled to, it is acetyloxy phenyl first between 20wt% that mass fraction, which is added dropwise, The tetrahydrofuran solution of acyl chlorides, is incubated 30min, and then reaction is quenched in watery hydrochloric acid, and stratification takes organic phase to be spin-dried for obtaining 3- second Acyloxy benzoyl diethyl malonate, wherein, the volume of diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride Weight (L/kg) is than being 15:2.8;
3- acetyloxy phenyl formylmaloic acids diethylester is added into mass fraction in the 10wt% p-methyl benzenesulfonic acid aqueous solution Mix, be warming up to 100 DEG C, flow back 5h, be cooled to 10 DEG C of crystallizations, centrifugation obtains m-hydroxy acetophenone, wherein, sulfuric acid and 3- acetyl The weight ratio of epoxide benzoyl diethyl malonate is 5:1.
Embodiment 4
A kind of preparation method of m-hydroxy acetophenone, comprises the following steps:M-hydroxybenzoic acid is added in dichloromethane Dissolving, adds acetic anhydride and lead acetate, is warming up to 30 DEG C, is incubated 4h, and cooling separates out solid, and filtering, drying obtains an acetyl oxygen Yl benzoic acid, wherein, the mol ratio of m-hydroxybenzoic acid and acetic anhydride is 1.5:1, mole of lead acetate and m-hydroxybenzoic acid Than for 0.1:100, the weight ratio of dichloromethane and m-hydroxybenzoic acid is 2:1;
In nitrogen atmosphere, acetoxy-benzoic acid, ether are mixed by between, add DMF, are added dropwise two Chlorine sulfoxide, is warming up to 25 DEG C, is incubated 8h, is concentrated to give an acetoxyl group chlorobenzoyl chloride, wherein, an acetoxy-benzoic acid and two The mol ratio of chlorine sulfoxide is 2.5:1, the mol ratio of DMF and an acetoxy-benzoic acid is 2:100;
Dichloromethane, diethyl malonate are mixed, stirring adds sodium methoxide, is warming up to 30 DEG C, insulation 8h obtains the third two Diethyl phthalate sodium salt solution, wherein, the mol ratio of diethyl malonate and sodium methoxide is 1:5, dichloromethane and malonic acid diethyl The weight ratio of ester is 10:1;
Diethyl malonate sodium salt solution is taken, 0 DEG C is cooled to, it is acetyloxy phenyl first between 16.7wt% that mass fraction, which is added dropwise, The dichloromethane solution of acyl chlorides, is incubated 2h, and then reaction is quenched in watery hydrochloric acid, and stratification takes organic phase to be spin-dried for obtaining 3- acetyl Epoxide benzoyl diethyl malonate, wherein, the volume weight of diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride (L/kg) is measured than being 15:2.73;
3- acetyloxy phenyl formylmaloic acids diethylester is added in aqueous acetic acid and mixed, 90 DEG C are warming up to, flow back 4h, Cool crystallization, and centrifugation obtains m-hydroxy acetophenone, wherein, the weight ratio of acetic acid and 3- acetyloxy phenyl formylmaloic acid diethylesters For 10:1.
Embodiment 5
A kind of preparation method of m-hydroxy acetophenone, comprises the following steps:M-hydroxybenzoic acid is added in toluene and dissolved, Acetic anhydride and ammonium acetate are added, 100 DEG C are warming up to, 3h is incubated, cooling separates out solid, and filtering, drying obtains an acetyloxy phenyl Formic acid, wherein, the mol ratio of m-hydroxybenzoic acid and acetic anhydride is 1.3:1, the mol ratio of ammonium acetate and m-hydroxybenzoic acid is 0.3:100, the weight ratio of toluene and m-hydroxybenzoic acid is 4:1;
In nitrogen atmosphere, acetoxy-benzoic acid, toluene are mixed by between, add DMF, are added dropwise two Chlorine sulfoxide, is warming up to 80 DEG C, is incubated 2h, is concentrated to give an acetoxyl group chlorobenzoyl chloride, wherein, an acetoxy-benzoic acid and two The mol ratio of chlorine sulfoxide is 1.5:1, the mol ratio of DMF and an acetoxy-benzoic acid is 4:100;
Toluene, diethyl malonate are mixed, stirring adds caustic alcohol, are warming up to 100 DEG C, insulation 3h obtains malonic acid two Ethyl ester sodium salt solution, wherein, the mol ratio of diethyl malonate and caustic alcohol is 1:3, the weight of toluene and diethyl malonate Than for 1:1;
Diethyl malonate sodium salt solution is taken, -5 DEG C are cooled to, it is acetyloxy phenyl between 33.3wt% that mass fraction, which is added dropwise, The toluene solution of formyl chloride, is incubated 1h, and then reaction is quenched in watery hydrochloric acid, and stratification takes organic phase to be spin-dried for obtaining 3- acetyl oxygen Base benzoyl diethyl malonate, wherein, the volume weight of diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride (L/kg) than being 15:2.77;
3- acetyloxy phenyl formylmaloic acids diethylester is added in aqueous hydrochloric acid solution and mixed, 110 DEG C, backflow are warming up to 1h, cool crystallization, and centrifugation obtains m-hydroxy acetophenone, wherein, the weight of hydrochloric acid and 3- acetyloxy phenyl formylmaloic acid diethylesters Amount is than being 7.5:1.
Embodiment 6
A kind of preparation method of m-hydroxy acetophenone, comprises the following steps:M-hydroxybenzoic acid is added in ether and dissolved, Acetic anhydride and sodium acetate are added, 32 DEG C are warming up to, 2.5h is incubated, cooling separates out solid, and filtering, drying obtains an acetyloxy phenyl Formic acid, wherein, the mol ratio of m-hydroxybenzoic acid and acetic anhydride is 1.4:1, the mol ratio of sodium acetate and m-hydroxybenzoic acid is 0.4:100, the weight ratio of ether and m-hydroxybenzoic acid is 5:1;
In nitrogen atmosphere, acetoxy-benzoic acid, tetrahydrofuran are mixed by between, add DMF, drop Plus thionyl chloride, 50 DEG C are warming up to, 7h is incubated, is concentrated to give an acetoxyl group chlorobenzoyl chloride, wherein, an acetoxy-benzoic acid Mol ratio with thionyl chloride is 2:1, the mol ratio of DMF and an acetoxy-benzoic acid is 3:100;
Ether, diethyl malonate are mixed, stirring adds sodium hydroxide, are warming up to 31 DEG C, insulation 6h obtains malonic acid Diethylester sodium salt solution, wherein, the mol ratio of diethyl malonate and sodium hydroxide is 1:2, ether and diethyl malonate Weight ratio is 2:1;
Diethyl malonate sodium salt solution is taken, -8 DEG C are cooled to, it is acetyloxy phenyl first between 30wt% that mass fraction, which is added dropwise, The diethyl ether solution of acyl chlorides, is incubated 1.5h, and then reaction is quenched in watery hydrochloric acid, and stratification takes organic phase to be spin-dried for obtaining 3- acetyl oxygen Base benzoyl diethyl malonate, wherein, the volume weight of diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride (L/kg) than being 15:2.75;
3- acetyloxy phenyl formylmaloic acids diethylester is added in aqueous sulfuric acid and mixed, 95 DEG C are warming up to, flow back 4h, Cool crystallization, and centrifugation obtains m-hydroxy acetophenone, wherein, the weight ratio of sulfuric acid and 3- acetyloxy phenyl formylmaloic acid diethylesters For 6:1.
Embodiment 7
A kind of preparation method of m-hydroxy acetophenone, comprises the following steps:M-hydroxybenzoic acid is added to the water dissolving, plus Enter acetic anhydride and zinc acetate, be warming up to 90 DEG C, be incubated 2.5h, cooling separates out solid, and filtering, drying obtains an acetyloxy phenyl first Acid, wherein, the mol ratio of m-hydroxybenzoic acid and acetic anhydride is 1.2:1, the mol ratio of zinc acetate and m-hydroxybenzoic acid is 0.2:100, the weight ratio of water and m-hydroxybenzoic acid is 9:1;
In nitrogen atmosphere, acetoxy-benzoic acid, water are mixed by between, add DMF, and dichloro is added dropwise Sulfoxide, is warming up to 85 DEG C, is incubated 4h, is concentrated to give an acetoxyl group chlorobenzoyl chloride, wherein, an acetoxy-benzoic acid and dichloro The mol ratio of sulfoxide is 1.8:1, the mol ratio of DMF and an acetoxy-benzoic acid is 1.5:100;
Dichloroethanes, diethyl malonate are mixed, stirring adds sodium methoxide, is warming up to 75 DEG C, insulation 7h obtains the third two Diethyl phthalate sodium salt solution, wherein, the mol ratio of diethyl malonate and sodium methoxide is 1:3, dichloroethanes and malonic acid diethyl The weight ratio of ester is 7:1;
Diethyl malonate sodium salt solution is taken, the dichloroethanes for being cooled to acetoxyl group chlorobenzoyl chloride between -2 DEG C, dropwise addition is molten Liquid, is incubated 2.2h, and then watery hydrochloric acid is quenched reaction, stratification, takes organic phase to be spin-dried for obtaining 3- acetoxyl groups benzoyl the third two Diethyl phthalate, wherein, the volume weight (L/kg) of diethyl malonate sodium salt solution and an acetoxyl group chlorobenzoyl chloride is than being 15: 2.75;
3- acetyloxy phenyl formylmaloic acids diethylester is added in the p-methyl benzenesulfonic acid aqueous solution and mixed, 100 DEG C are warming up to, Flow back 3h, and cool crystallization, and centrifugation obtains m-hydroxy acetophenone, wherein, p-methyl benzenesulfonic acid and 3- acetyloxy phenyl formylmaloic acids The weight ratio of diethylester is 7:1.
Purity to the embodiment 1-7 m-hydroxy acetophenones prepared is detected, and counts yield, as a result as follows:
High income of the present invention as can be seen from the above table, the purity of the m-hydroxy acetophenone prepared is good.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto, Any one skilled in the art the invention discloses technical scope in, technique according to the invention scheme and its Inventive concept is subject to equivalent substitution or change, should all be included within the scope of the present invention.

Claims (10)

1. a kind of preparation method of m-hydroxy acetophenone, it is characterised in that comprise the following steps:By m-hydroxybenzoic acid acetylation An acetoxy-benzoic acid is obtained, then chloride obtains an acetoxyl group chlorobenzoyl chloride, it is then molten with diethyl malonate sodium salt Liquid reaction obtains 3- acetyloxy phenyl formylmaloic acid diethylesters, and last decarboxylation obtains m-hydroxy acetophenone.
2. the preparation method of m-hydroxy acetophenone according to claim 1, it is characterised in that in acetylation, a hydroxyl Yl benzoic acid carries out acetylization reaction with acetylation reagent, wherein, acetylation reagent is acetic anhydride;Preferably, a hydroxy benzenes first The mol ratio of acid and acetylation reagent is 1-1.5:1.
3. the preparation method of m-hydroxy acetophenone according to claim 1 or claim 2, it is characterised in that in acetylation also Acetylation catalyst need to be added, wherein, acetylation catalyst is at least one in sodium acetate, ammonium acetate, zinc acetate, lead acetate Kind;Preferably, the mol ratio of acetylation catalyst and m-hydroxybenzoic acid is 0.1-0.5:100.
4. according to the preparation method of any one of the claim 1-3 m-hydroxy acetophenones, it is characterised in that the reaction of acetylation Solvent is at least one of toluene, dichloromethane, ether, dichloroethanes, water, tetrahydrofuran;Preferably, the reaction of acetylation The weight ratio of solvent and m-hydroxybenzoic acid is 2-10:1;Preferably, the temperature of acetylation is 30-100 DEG C, and the time is 2-4h.
5. according to the preparation method of any one of the claim 1-4 m-hydroxy acetophenones, it is characterised in that in chloride process In, an acetoxy-benzoic acid carries out acyl chloride reaction with chloride reagent, wherein, chloride reagent is thionyl chloride;It is preferred that The mol ratio of ground, an acetoxy-benzoic acid and chloride reagent is 1-2.5:1.
6. according to the preparation method of any one of the claim 1-5 m-hydroxy acetophenones, it is characterised in that in chloride process In also need add chloride catalyst, wherein, chloride catalyst be DMF;Preferably, chloride is catalyzed The mol ratio of agent and an acetoxy-benzoic acid is 1-5:100.
7. according to the preparation method of any one of the claim 1-6 m-hydroxy acetophenones, it is characterised in that the reaction of chloride Solvent is at least one of toluene, ether, dichloromethane, dichloroethanes, water, tetrahydrofuran, ethanol;Preferably, chloride Reaction dissolvent be high boiling solvent;Preferably, the reaction dissolvent of chloride is ethanol or/and tetrahydrofuran;Preferably, acyl chlorides The temperature of change is 25-80 DEG C, and the time is 2-8h.
8. according to the preparation method of any one of the claim 1-7 m-hydroxy acetophenones, it is characterised in that in malonic acid diethyl In the preparation process of ester sodium salt solution, diethyl malonate reacts with alkaline matter containing sodium in the first solvent obtains malonic acid two Ethyl ester sodium salt solution;Preferably, alkaline matter containing sodium is at least one in caustic alcohol, sodium methoxide, sodium hydroxide, sodium acid carbonate Kind;Preferably, the first solvent is at least one of toluene, dichloromethane, dichloroethanes, ether, tetrahydrofuran, ethanol;It is excellent Selection of land, the first solvent is tetrahydrofuran or/and ether;Preferably, the mol ratio of diethyl malonate and the alkaline matter containing sodium is 1:1-5;Preferably, the weight ratio of the first solvent and diethyl malonate is 1-10:1;Preferably, diethyl malonate is with containing sodium The temperature of alkali substance reaction is 30-100 DEG C, and the time is 3-8h.
9. according to the preparation method of any one of the claim 1-8 m-hydroxy acetophenones, it is characterised in that in malonic acid diethyl In ester sodium salt solution and an acetoxyl group chlorobenzoyl chloride course of reaction, diethyl malonate sodium salt solution and an acetyloxy phenyl first Solution of acid chloride is reacted, wherein, the solvent of an acetoxyl group chlorobenzoyl chloride solution is the first solvent;Preferably, malonic acid two The volume weight (L/kg) of ethyl ester sodium salt solution and an acetoxyl group chlorobenzoyl chloride is than being 15:2.7-2.8;Preferably, malonic acid The temperature that diethylester sodium salt solution and an acetoxyl group chlorobenzoyl chloride react is -10 to 0 DEG C, and the time is 30min-2h.
10. according to the preparation method of any one of the claim 1-9 m-hydroxy acetophenones, it is characterised in that decarboxylation need to be in acid Property environment in carry out;Preferably, sour environment is maintained with acidic materials, wherein, acidic materials are hydrochloric acid, sulfuric acid, acetic acid, right At least one of toluenesulfonic acid;Preferably, the weight ratio of acidic materials and 3- acetyloxy phenyl formylmaloic acid diethylesters is 5-10:1;Preferably, decarboxylation need to be carried out in acidic aqueous solution;Preferably, the temperature of decarboxylation is 90-110 DEG C, and the time is 1- 5h。
CN201710451177.7A 2017-06-15 2017-06-15 A kind of preparation method of m-hydroxy acetophenone Pending CN107118088A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710451177.7A CN107118088A (en) 2017-06-15 2017-06-15 A kind of preparation method of m-hydroxy acetophenone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710451177.7A CN107118088A (en) 2017-06-15 2017-06-15 A kind of preparation method of m-hydroxy acetophenone

Publications (1)

Publication Number Publication Date
CN107118088A true CN107118088A (en) 2017-09-01

Family

ID=59718381

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710451177.7A Pending CN107118088A (en) 2017-06-15 2017-06-15 A kind of preparation method of m-hydroxy acetophenone

Country Status (1)

Country Link
CN (1) CN107118088A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108530277A (en) * 2018-05-21 2018-09-14 江西永通科技股份有限公司 A kind of preparation method of m-hydroxy acetophenone
CN113666819A (en) * 2020-05-14 2021-11-19 帕潘纳(北京)科技有限公司 Method for preparing chlorofluoromethrizole intermediate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105967986A (en) * 2016-05-30 2016-09-28 北京旭阳科技有限公司 3-hydroxyacetophenone synthesis method

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105967986A (en) * 2016-05-30 2016-09-28 北京旭阳科技有限公司 3-hydroxyacetophenone synthesis method

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SACHIN B. UNDRE ET AL.: "Silibinin Binding and Release Activities Moderated by Interstices of Trimesoyl, Tridimethyl, and Tridiethyl Malonate First-Tier Dendrimers", 《JOURNAL OF APPLIED POLYMER》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108530277A (en) * 2018-05-21 2018-09-14 江西永通科技股份有限公司 A kind of preparation method of m-hydroxy acetophenone
CN113666819A (en) * 2020-05-14 2021-11-19 帕潘纳(北京)科技有限公司 Method for preparing chlorofluoromethrizole intermediate
CN113666819B (en) * 2020-05-14 2024-06-21 帕潘纳(北京)科技有限公司 Method for preparing penconazole intermediate

Similar Documents

Publication Publication Date Title
CN106008290A (en) Method for preparing tembotrions
CN105330568B (en) Preparation method for p-aminobenzamidine hydrochloride
CN107473949A (en) A kind of synthesis technique of the pentanone of 3,5 dichloro 2
CN107118088A (en) A kind of preparation method of m-hydroxy acetophenone
CN101270124B (en) Novel method for purifying and preparing high-purity fluorandiol and fluorandiol salt
CN113336764B (en) Bipyridine ligand with axial chirality and synthetic method thereof
CN111004205A (en) Synthetic method for preparing piperonyl butoxide under catalysis of composite alkali
CN102942532A (en) Preparation method of 1,4,7,10-tetraazadodecane
CN105237389A (en) Method for preparing hypolipidemic medicine ciprofibrate with p-coumaric acid
CN101955415B (en) Method for preparing 2-hydroxyl biphenyl compound
CN105294415A (en) Preparation method of 3-halogenated fluorenone compound
CN114315575A (en) Preparation method and application of photoinitiator intermediate
CN113061072A (en) Method for preparing 1-cyclopropyl naphthalene
CN102167667A (en) Method for synthesizing pentaerythritol tetrabenzoate
CN106518687A (en) Efficient preparation method of high-purity tetraethyl ammonium chloride
CN106316950A (en) Gliquidone preparation method
CN102086147B (en) Preparation method of substituted phenol
CN107382640A (en) The synthetic method of β aryl phenylpropyl alcohol ketone class compounds
CN105175250B (en) A kind of new method synthesizing ciprofibrate
CN102977012B (en) Synthesis method of methyl 4-bromopyridyl-2-formate
CN102557947B (en) Method for preparing 5-bromoacetylsalicylic acid methyl ester
CN112390749A (en) Synthesis method of cabozantinib and intermediate thereof
CN105481662B (en) The method for preparing the intermediate for producing the liquid-crystal compounds containing difluoro-methoxy
CN103833530A (en) Preparation method of organic intermediate 3-phenoxyl-1, 2-propylene glycol
CN105330633A (en) Preparation method for biphenyltetracarboxylic dianhydride mixture

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20170901

RJ01 Rejection of invention patent application after publication