CN100564339C - 2, the preparation method of 3-two fluoro-5-bromophenols - Google Patents
2, the preparation method of 3-two fluoro-5-bromophenols Download PDFInfo
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- CN100564339C CN100564339C CNB2007100402724A CN200710040272A CN100564339C CN 100564339 C CN100564339 C CN 100564339C CN B2007100402724 A CNB2007100402724 A CN B2007100402724A CN 200710040272 A CN200710040272 A CN 200710040272A CN 100564339 C CN100564339 C CN 100564339C
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Abstract
The present invention relates to 2, the preparation method of 3-two fluoro-5-bromophenols, comprise: (1) is with 2,3, the 4-trifluoronitrobenzene is a raw material, is prepared as follows two fluoro nitro-paraffin oxygen base benzene: (i) make 2,3, the alkyl alkoxide of 4-trifluoronitrobenzene and basic metal or alkaline-earth metal carries out substitution reaction, and the alkyl in the described alkyl alkoxide is C
1～C
7Alkyl; Or (ii) in the presence of alkali, make 2,3, and 4-trifluoronitrobenzene and alkyl alcohol carry out substitution reaction, and the alkyl in the described alkyl alcohol is C
1～C
7Alkyl; (2) with reductive agent two fluoro nitro-paraffin oxygen base benzene are reduced into two fluoro alkoxyl anilines; (3) be difluoro bromo alkoxyl aniline with bromizating agent with two fluoro alkoxyl aniline brominations; (4) difluoro bromo alkoxyl aniline is obtained 2,3-two fluoro-5-bromine alkoxy benzenes through diazotization and desamination reaction successively; (5) with 2,3-two fluoro-5-bromine alkoxy benzenes obtain 2 after taking off ehter bond, 3-two fluoro-5-bromophenols.This method can be with comparatively simple technology, and than the lower cost of prior art, higher yields and high purity make 2,3-two fluoro-5-bromophenol products.
Description
Technical field
The present invention relates to 2, the preparation method of 3-two fluoro-5-bromophenols.
Background technology
2,3-two fluoro-5-bromophenols are the important fluorinated liquid crystal intermediates in a kind of half transmitting liquid crystal (TFT) display equipment of novel low voltage less energy-consumption.This compound can be represented with following chemical formula.
2,3-two fluoro-5-bromophenols are the increasingly extensive intermediates of a kind of purposes, are the intermediates of synthesizing compound of liquid crystal, pharmaceutical compound and the agricultural chemical compound used always.
The method for preparing phenol has several, and the method for introducing hydroxyl commonly used has:
1) halogenide hydrolysis
2) aromatic sulfonic acid salt alkali fusion
3) aryl primary amine and diazonium salt hydrolysis
4) on aromatic ring, directly introduce the method that nucleophilic substitution reaction such as hydroxyl prepares alcohol and phenolic compound.
It is a kind of 2 that CN200510130822.2 has reported, the preparation method of 3-two fluoro-5-bromophenols, this method are with 2, and the 3-difluoroanisole is a raw material, and through nitrated, reduction, bromo, deaminizating, demethylation obtains final product 2,3-two fluoro-5-bromophenols.But the deficiency that this method exists is: (i) total recovery is lower, and each goes on foot total recovery is 34.9%; (ii) raw material 2, and the 3-difluoroanisole costs an arm and a leg; The possibility that (iii) has isomers in the sintetics of this route is unfavorable for TFT liquid crystal monocrystalline requirement of high purity.
Summary of the invention
The object of the present invention is to provide a kind of 2, the preparation method of 3-two fluoro-5-bromophenols, this method can be with comparatively simple technology, than the lower cost of prior art, higher yields and high purity make 2,3-two fluoro-5-bromophenol products.
The present inventor finds after having carried out deep research, the present invention has adopted the good trifluoronitrobenzene of orientation effect as raw material, avoided the generation of isomer, thereby made the yield of the finished product improve greatly, each goes on foot total recovery can reach 60% or higher.More specifically be, with 2,3, the 4-trifluoronitrobenzene is a raw material, pass through alkoxyl group replacement, reduction, bromo, deaminizating successively and take off the ehter bond reaction to obtain final product 2, and 3-two fluoro-5-bromophenols, and on this basis, finished the present invention.
The invention provides a kind of preparation 2, the method for 3-two fluoro-5-bromophenols, this method may further comprise the steps:
(1) with 2,3, the 4-trifluoronitrobenzene is a raw material, prepare two fluoro nitro-paraffin oxygen base benzene to be selected from any following mode: (i) make 2,3, the alkyl alkoxide of 4-trifluoronitrobenzene and basic metal or alkaline-earth metal carries out substitution reaction, and the alkyl in the described alkyl alkoxide is C
1～C
7Alkyl; (ii) in the presence of alkali, make 2,3,4-trifluoronitrobenzene and alkyl alcohol carry out substitution reaction, and the alkyl in the described alkyl alcohol is C
1～C
7Alkyl;
(2) with reductive agent the two fluoro nitro-paraffin oxygen base benzene that step (1) obtains are reduced into two fluoro alkoxyl anilines;
(3) be difluoro bromo alkoxyl aniline with bromizating agent with the two fluoro alkoxyl aniline brominations that step (2) obtains;
(4) the difluoro bromo alkoxyl aniline that step (3) is obtained obtains 2,3-two fluoro-5-bromine alkoxy benzenes through diazotization and desamination reaction successively;
(5) step (4) is obtained 2,3-two fluoro-5-bromine alkoxy benzenes obtain 2 after taking off ehter bond, 3-two fluoro-5-bromophenols.
In aforesaid method, preferably, the alkyl alkoxide of described basic metal or alkaline-earth metal is selected from sodium alkyl alcohol or alkyl potassium alcoholate.
In aforesaid method, preferably, described alkali is the oxyhydroxide of basic metal or alkaline-earth metal or the alkyl alkoxide of basic metal or alkaline-earth metal, and wherein, the alkyl of described alkyl alkoxide is C
1～C
7Alkyl; Be preferably, described alkali is to be selected from one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta, lithium hydroxide, sodium alkyl alcohol or alkyl potassium alcoholate.
In aforesaid method, preferably, the alkyl alkoxide of described basic metal or alkaline-earth metal and the alkyl in the described alkyl alcohol are C
1～C
5Alkyl; Preferred, the alkyl alkoxide of described basic metal or alkaline-earth metal and the alkyl in the described alkyl alcohol are C
1～C
3Alkyl.
In aforesaid method, preferably, the temperature of reaction of step (1) is in-20 ℃～150 ℃ scope; More preferably, the temperature of reaction of step (1) is in 20 ℃～80 ℃ scope.
In aforesaid method, preferably, in the step (1), the alkyl alkoxide of reactant basic metal or alkaline-earth metal or the usage quantity of alkyl alcohol are equivalent to 2,3,0.5～5 times of molar weight of 4-trifluoronitrobenzene; More preferably, the alkyl alkoxide of reactant basic metal or alkaline-earth metal or the usage quantity of alkyl alcohol are equivalent to 2,3,1～2 times of molar weight of 4-trifluoronitrobenzene.
In aforesaid method, preferably, step (1) is carried out in the presence of solvent, solvent for use is to be selected from following one or more: ethanol, sherwood oil, methyl tertiary butyl ether, acetonitrile, toluene, benzene, ethyl acetate, N, dinethylformamide, ethylene dichloride, chloroform or N-Methyl pyrrolidone.
In aforesaid method, preferably, step (2) is carried out in the presence of solvent, solvent for use is to be selected from following one or more: ethanol, sherwood oil, methyl tertiary butyl ether, acetonitrile, toluene, benzene, ethyl acetate, N, dinethylformamide, ethylene dichloride, chloroform or N-Methyl pyrrolidone.
In aforesaid method, preferably, step (3) is carried out in the presence of solvent, and solvent for use is to be selected from following one or more: ethanol, sherwood oil, acetonitrile, toluene, benzene, ethyl acetate, dimethyl formamide (DMF), N-Methyl pyrrolidone.
In aforesaid method, preferably, step (5) is carried out in the presence of solvent, and solvent for use is to be selected from following one or more: mercaptan, propylmercaptan, isopropyl mercaptan, dimethyl sulfoxide (DMSO), tetramethylene sulfone, ethylene dichloride.
In aforesaid method, preferably, the described reductive agent that uses in the step (2) is to be selected from following one or more: hydrogen, iron powder, zinc powder, lithium aluminum hydride or Raney's nickel.
In aforesaid method, preferably, the temperature of reaction of step (2) is in-10 ℃～150 ℃ scope; Be more preferably, the temperature of reaction of step (2) is in 30 ℃～90 ℃ scope.
Description of drawings
Fig. 1 make for the embodiment of the invention 12,3-two fluoro-5-bromophenols
1The H-NMR spectrogram.
Embodiment
As mentioned above, technical scheme of the present invention is with 2,3, and the 4-trifluoronitrobenzene is a raw material, passes through alkoxyl group replacement, reduction, bromo, deaminizating successively and take off the ehter bond reaction to obtain final product 2,3-two fluoro-5-bromophenols.A kind of concrete embodiment is shown in following reaction formula.Should be appreciated that these reaction formula just are used for illustrating of the present invention, protection domain are not construed as limiting.
In this application, term " alkyl " expression straight or branched alkyl.Term " alkoxyl group " separately or combining form represent general formula R O.Wherein, the alkyl R in alkyl or the alkoxyl group is preferably C
1-C
7Alkyl, more preferably C
1～C
5Alkyl is preferably C especially
1～C
3Alkyl.
Term " alkyl alcohol " is used for representing an alcohol, glycol or how pure.The used alkyl alcohol of the present invention is C preferably
1-C
7Alkyl alcohol is more preferably C
1-C
5Alkyl alcohol, such as but not limited to: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, ethylene glycol, Diethylene Glycol etc.
Below each step of preparation method of the present invention is elaborated respectively.
Step 1 (alkoxyl group replacement)
This step is with 2,3, and the alkyl alkoxide of 4-trifluoronitrobenzene and alkyl alcohol or basic metal or alkaline-earth metal is a raw material, and these all are the products that can buy from the market.2,3, the 4-trifluoronitrobenzene can for example be but be not limited to: available from 2,3 of the magnificent chemical plant that shakes, Wujin, Jiangsu, the 4-trifluoronitrobenzene is available from Shanghai 2,3 of the chemical industry company limited of delivering a letter, 4-trifluoronitrobenzene; Alkyl alcohol can for example be but be not limited to: available from methyl alcohol, ethanol (95%), propyl carbinol, ethylene glycol, the Virahol of Kunshan Jin Cheng reagent company limited; Methyl alcohol, ethanol (anhydrous), propyl carbinol, Virahol, ethylene glycol, Diethylene Glycol available from Changzhou ten thousand and chemical industry trade Co., Ltd; The alkyl alkoxide of basic metal or alkaline-earth metal can for example be but be not limited to: available from Shanghai unite sodium methylate, the sodium ethylate of inferior chemical science and technology Development Co., Ltd.
The alkyl alkoxide of basic metal or alkaline-earth metal is sodium alkyl alcohol or alkyl potassium alcoholate preferably, is more preferably sodium methylate, sodium ethylate, n-propyl alcohol sodium, sodium isopropylate, propyl carbinol sodium, isobutyl sodium alkoxide, sodium tert-butoxide, potassium methylate, potassium ethylate, n-propyl alcohol potassium, potassium isopropoxide, propyl carbinol potassium, isobutyl potassium alcoholate or potassium tert.-butoxide.
Alkyl alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, ethylene glycol, Diethylene Glycol preferably.
The alkyl alkoxide of basic metal or alkaline-earth metal or the consumption of alkyl alcohol do not have particular requirement, and preferred usage quantity is equivalent to 2,3,0.5～5 times of molar weight of 4-trifluoronitrobenzene, more preferably 1～2 times of molar weight.Under above-mentioned consumption, can improve initial compounds 2,3, the reaction efficiency of 4-trifluoronitrobenzene makes things convenient for post-processing operation.
Reaction temperature is spent and low can be influenced speed of response, and when temperature is lower than-20 ℃, substitution reaction is normally advanced than difficulty, improve temperature of reaction and can increase speed of response, but can influence the selectivity of alkoxyl group substitution reaction, cause that secondary replaces, and the growing amount of increase high boiling product, reduce product yield.Temperature of reaction is preferably-20 ℃～150 ℃, wherein more preferably 20 ℃～80 ℃.Under preferred temperature of reaction, the product yield of substitution reaction can reach more than 90%, and no isomer generates in the reaction process, and a spot of high product that boils is only arranged.
Alkali is mineral alkali or organic bases, wherein the oxyhydroxide of mineral alkali preferred as alkali or alkaline-earth metal, more preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta or lithium hydroxide, most preferably potassium hydroxide; Organic bases refers to the alkyl alkoxide of basic metal or alkaline-earth metal, preferred alkyl sodium alkoxide or alkyl potassium alcoholate.As long as the consumption of alkali can guarantee that this is reflected under the alkaline condition, there is not particular requirement, preferably be equivalent to 2,3,0.5～5 times of molar weight of 4-trifluoronitrobenzene.
Substitution reaction is carried out in solvent, can use any solvent that reaction is had no adverse effects, as alcohols, ethers, nitrile, aromatic compound, ester class, halohydrocarbon, aprotic polar solvent, wherein preferred alcohol, acetonitrile, sherwood oil, toluene, benzene, ethyl acetate, dimethyl formamide (DMF), ethylene dichloride, chloroform or N-Methyl pyrrolidone, more preferably toluene.The consumption of solvent does not have particular requirement, only otherwise stable the getting final product of influence reaction.Preferred solvent load is 2,3,0.5～5 times of molar weight of 4-trifluoronitrobenzene.
Can adopt ordinary method (as gas-chromatography etc.) that the performance level of reaction is carried out tracking monitor.Reaction times is depended on temperature of reaction, solvent and concrete reactant, under above-mentioned preferred reaction conditions, generally can finish reaction about 1-6 hour.
Step 2 (reduction reaction)
The reductive mode can be that metal adds acid or catalytic hydrogenation method.Available metallic reducing agent includes but not limited to iron powder, zinc powder, lithium aluminum hydride, Raney's nickel, wherein preferred iron powder, and acid can be adopted hydrochloric acid, sulfuric acid or acetic acid etc.Under the hydrogenating reduction condition, can use hydrogenation catalysts commonly used such as nickel, platinum, palladium, as palladium/carbon, platinum/carbon or Raney's nickel etc.In order to impel reduction reaction to finish within a short period of time, improve reaction efficiency, the preferable amount of reductive agent is equivalent to 1.0～3.5 times of molar weights of two fluoro nitro-paraffin oxygen base benzene.
Be reflected in the solvent and carry out, can use any solvent that reaction is had no adverse effects, as alcohols, ethers, nitrile, aromatic compound, ester class, aprotic polar solvent, wherein the preferred alcohol aqueous solution, ethanol, sherwood oil, acetonitrile, toluene, benzene, ethyl acetate, dimethyl formamide (DMF), N-Methyl pyrrolidone, more preferably aqueous ethanolic solution.
The consumption of solvent does not have particular requirement, only otherwise stable the getting final product of influence reaction.Preferred solvent load is 1～2 times of molar weight of two fluoro nitro-paraffin oxygen base benzene.
Temperature of reaction does not have particular requirement, and preferred-10 ℃～150 ℃, more preferably 30 ℃～90 ℃, under preferred temperature, can obtain good reaction efficiency, the product yield of reduction reaction can reach about 90%.
Can adopt ordinary method (as thin-layer chromatography etc.) that the performance level of reaction is carried out tracking monitor.Reaction times is depended on temperature of reaction, solvent and concrete reactant, under above-mentioned preferred reaction conditions, generally can finish reaction about 1-8 hour.
Step (3) (bromo-reaction)
Reaction is preferably carried out in organic solvent.Can use any solvent that reaction is had no adverse effects, as alcohols, ethers, nitrile, aromatic compound, ester class, aprotic polar solvent, wherein preferred alcohol, sherwood oil, acetonitrile, toluene, benzene, ethyl acetate, dimethyl formamide (DMF), N-Methyl pyrrolidone, more preferably ethanol.
The consumption of solvent does not have particular requirement, only otherwise stable the getting final product of influence reaction.Preferred solvent load is 1～2 times of molar weight of two fluoro aminoalkoxy benzene.
Temperature of reaction does not have particular requirement, and preferred-10 ℃～150 ℃, more preferably 30 ℃～90 ℃, under preferred temperature, can obtain good reaction efficiency, the product yield of bromination reaction can reach about 85%.
Can adopt ordinary method (as thin-layer chromatography etc.) that the performance level of reaction is carried out tracking monitor.Reaction times is depended on temperature of reaction, solvent and concrete reactant, under above-mentioned preferred reaction conditions, generally can finish reaction about 1-8 hour.
Step 4 (diazotization and desamination reaction)
Adopt the operation of conventional diazotization reaction and desamination reaction, for example in the diazotization reaction, diazo reagent adopts NaNO
2Or nitrous acid ester, difluoro bromo alkoxyl aniline is dissolved in the acid salify and preferably carries out (described room temperature is generally 10-30 ℃) about room temperature to 80 ℃, and diazotization reaction is carried out for preferred about-20 ℃～5 ℃.Deamination reagent adopts Virahol, ortho phosphorous acid sodium water solution, Hypophosporous Acid, 50, ethanol etc., can adopt copper salt catalyst such as cupric oxide.Desamination reaction preferably carries out under-20 ℃～100 ℃.
Step 5 (taking off the ehter bond reaction)
Adopt the conventional operation that takes off ehter bond, the effect that utilizes Lewis acid and organic solvent is with 2, and 3-two fluoro-5-bromine alkoxy benzenes are converted into 2,3-two fluoro-5-bromophenols.
Reaction is preferably carried out in solvent.Can use any solvent that reaction is had no adverse effects,, but be not limited only to above-mentioned organic solvent as mercaptan, propylmercaptan, isopropyl mercaptan, dimethyl sulfoxide (DMSO) (DMSO), tetramethylene sulfone, ethylene dichloride etc.Taking off the ehter bond reaction preferably carries out under-20 ℃～100 ℃.
Target product 2,3-two fluoro-5-bromophenols can adopt methods such as ebulliometry, gaseous mass spectrum, nucleus magnetic resonance to detect affirmation.
In preparation method of the present invention, after finishing, each step reaction can directly carry out next step reaction.The intermediate product that also can adopt each step reaction of post processing mode separation and purification such as extraction, suction filtration, washing, drying, precipitation to obtain is to help improving the efficient of next step reaction.
Major advantage of the present invention is as follows:
(1) to have technology comparatively simple for preparation method's of the present invention synthesis path, and side reaction is few, and throughput is big, the reaction conditions gentleness, and cost is low, easily advantage such as suitability for industrialized production;
(2) commercialized raw materials of the employed raw material of preparation method of the present invention for cheaply being easy to get;
(3) preparation method of the present invention obtain 2, the purity of 3-two fluoro-5-bromophenol products can reach more than 99.5%, productive rate also is enhanced than prior art, each goes on foot productive rate and can reach about 85-90%, total recovery reaches about 55%-65%.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.
Among the following embodiment, vapor-phase chromatography is adopted in each degree of purity of production analysis, adopts GC-14B type gas chromatograph (Tianjin, island company) to measure, and chromatographic column is the BD-WAX post; Hydrogen flame detector, column temperature adopts temperature programming: the fs initial temperature (℃): 80, the initial temperature hold-time (min): 10, temperature rise rate (℃/min): 20, final temperature 210, temperature hold-time (min) eventually: 6.5; Carrier gas is a nitrogen, and carrier gas flux is 0.01MPa, and split stream injector,, 1/10 of splitting ratio: P=6mPa, sample size are 0.1 μ l.Adopting area normalization method to calculate measures.
The experimental technique of unreceipted actual conditions in the following example usually according to normal condition, or carries out according to the condition that manufacturer advises.Unless otherwise indicated, otherwise all umbers are weight part, and all per-cents are weight percentage.
Embodiment 1
The preparation of (1) two fluoro nitro phenetole
In the 2L four-hole bottle, drop into toluene 1100ml, KOH 140g (2.5mol) (95%) drops into 2 down at 25-35 ℃, 3, the mixture of 4-trifluoronitrobenzene 354g (2mol) (99.8%) and dehydrated alcohol 110g (2.4mol), 30 ℃ of following insulation reaction 2 hours, gas-chromatography (GC) tracked to raw material and finishes less than 1% reaction.Aftertreatment obtains the product 431g that weighs, and it is 85.73% that GC analyzes content.
The preparation of (2) two fluoro phenetidines
In the 2L four-hole bottle, drop into Fe powder 340g (6mol), 800g C
2H
5OH (95%), 200ml water drips two fluoro nitro phenetole (85.73%) 431g down at 75～78 ℃, dropwise about 30min, dropwise back insulation back flow reaction, reaction finishes about 4 hours, and sampling GC analyzes and tracks to raw material less than 1%, suction filtration after reaction finishes, washing, precipitation, distillation, get water white product 304.5g, sampling GC assay products content 97.38%.
The total recovery of step (1) and step (2) is 88%.
(3) preparation of difluoro bromo phenetidine
In the 2L four-hole bottle, drop into two fluoro phenetidine (97.38%): 304.5g (1.76mol) and ethylene dichloride: 1000ml, stir.Between 25-50 ℃, drip bromine water (Br
2) 155g (0.968mol), about 30min, drip off, drip off Br
230min is stirred in the back, begins to drip H
2O
2(27%) 134g (1.056mol), about 20min drips off, the insulation reaction GC assay products content 97.79% of taking a sample after half an hour.Reacted the saturated Na in back
2SO
3Wash, lower floor's organic phase is told in washing, and the organic phase precipitation is made short-path distillation, and 100～110 ℃/3mmHg steams product 385g, GC assay products content 98.8%.
Molar yield: 86%
The preparation of (4) 2,3-two fluoro-5-bromine oxethyl benzene
1, diazotization
At the 2L four-hole bottle, drop into HCl (30%)/H
2O:560g/560g (4.6mol) drips the about 10min of difluoro bromo phenetidine 385g (1.53mol) under stirring and drips off, and drips at 80 ℃ of insulation 15min, drips NaNO down at-5～0 ℃
2/ H
2O:110g/200ml (1.61mol) dropwised in about 1 hour, stirred 15min, and the next step is treated in insulation (5 ℃).
2, deaminizating
Add NaH at the 5L four-hole bottle
2PO
2.H
2O/H
2O:195g/120ml (1.836mol) and CuSO
45H
2O:2g is stirred in and drips above-mentioned diazonium liquid between 35-39 ℃, has a large amount of gas to emerge, and heat release dropwised in about 2 hours, stirred (at 35-39 ℃) half an hour, sampling GC assay products content 92.5%, layering, washing, precipitation; Molar yield=90%
The preparation of (5) 2,3-two fluoro-5-bromophenols
In the 2L four-hole bottle, drop into AlCl
3(anhydrous) 308g (2.3mol) and ethylene dichloride 750ml drip the about 5min of isopropyl mercaptan 122g (2.1mol) and drip off about 40 ℃, after dripping off 10min, between 25-30 ℃, drip 2,3-two fluoro-5-bromine oxethyl benzene (99.5%): 341g (1.44mol), about 20min drips off, reaction need be reacted the GC that finishes in 3-6 hour and be tracked to raw material less than 1% sampling GC analysis, product content 91.2%.
Acidifying after reaction finishes, washing, layering, the 288g that weighs behind the precipitation, sampling GC assay products content 93.5%
Molar yield: 87%
Total recovery: 59.2%
With the Brooker nuclear magnetic resonance analyser product that makes is analyzed, Fig. 1 shows the 1H-NMR spectrogram of embodiment 1 products therefrom, and concrete data are as follows:
1H-NMR(CDCl3，500MHz)δppm：
5.72(m，1H，-OH)6.93(m，1H，-H)6.88(m，1H，-H)
Embodiment 2
The preparation of (1) two fluoro nitro anisole:
In the reaction flask of 500ml, add 31.0g (0.55mol) potassium hydroxide, 250ml DMF, 38.5g (1.2mol) methyl alcohol, mix the back and drip 88.5g (0.5mol) 2 down at 145-150 ℃, 3, the 4-trifluoronitrobenzene, insulation reaction 2～4 hours adds 150ml water again, stir 15min, organic layer is got in layering, with mixed alkali liquor (10%NaOH/20%NaHCO
3) to neutral, desolventize through anhydrous magnesium sulfate drying, Rotary Evaporators steaming, obtain weak yellow liquid two fluoro nitro anisole 90.0g (0.47mol), molar yield: 71%, after measured, purity is 83%.
Step (2)-(5)
The operational condition of step (2)-(5) obtains colourless transparent liquid 2 with embodiment 1, and 3-two fluoro-5-bromophenol 75.0g measure through GC, and purity is 98%, and total recovery is 64.6%.
Embodiment 3
The preparation of (1) two fluoro nitro phenetole:
In the reaction flask of 1000ml, add 59.0g (1.05mol) potassium hydroxide, 550ml toluene, 57.5g (1.25mol) ethanol, at room temperature drip 177.0g (1mol) 2 after the mixing, 3, the 4-trifluoronitrobenzene, insulation reaction 1～2 hour adds 300ml water again, stir 15min, organic layer is got in layering, with mixed alkali liquor (10%NaOH/20%NaHCO
3) to neutral, desolventize through anhydrous magnesium sulfate drying, Rotary Evaporators steaming, obtain light yellow liquid two fluoro nitro phenetole 202.0g (0.99mol), molar yield: 99%, after measured, purity is 97%.
The preparation of (2) two fluoro phenetidines:
Method a, in the reaction flask of 1000ml, add 168.0g (3mol) iron powder, 400ml ethanol and 10ml 30% hydrochloric acid, stir half an hour down at 70 ℃, drip 202.0g (0.99mol) two fluoro nitro phenetoles, about 20min dropwises, afterreaction was complete in 4 hours, be cooled to room temperature, suction filtration is got filtrate, steams with Rotary Evaporators to desolventize back distillation (vacuum tightness 22mmHg, 110 ℃ of top temperature) obtain yellowish brown liquid two fluoro phenetidine 150.7g (0.87mol), molar yield 88%, after measured, purity is 98.6%.
Method b. mixes 400ml ethanol and 200.0g (0.985mol) two fluoro nitro phenetoles in the autoclave of 1000ml, add 5% palladium/carbon catalyst 10g, nitrogen replacement (nitrogen is full of reactor and excessive slightly) back feeds hydrogen, is heated to 40～50 ℃, keeps 5kgf/cm
2Pressure, afterreaction was complete in 8 hours, was cooled to room temperature, filtered, get filtrate, desolventize back distillation (vacuum tightness 30mmHg, 120 ℃ of top temperature), obtain yellowish brown liquid two fluoro phenetidine 161.0g (0.93mol) with the Rotary Evaporators steaming, molar yield 94%, after measured, purity is 95.6%.
Step (3)-(5):
The operational condition of step (3)-(5) obtains colourless transparent liquid 2 with embodiment 1,3-two fluoro-5-bromophenol 155.0g, and after measured, purity is 96%, total recovery is 65.4%.
Embodiment 4
Remove in the operation of (1) step and use propyl alcohol and propyl alcohol and 2,3, the mol ratio of 4-trifluoronitrobenzene is 1.3: 1, and other operational condition is identical with embodiment 1, obtains 2,3-two fluoro-5-bromophenol 145.0g, and molar yield 95%, after measured, purity is 99.5%.(1) step operation prepared 2, the purity of 3-two fluoro-6-nitro propoxy-benzene is 96%, yield 88%.
Embodiment 5
The diazotization reaction temperature of removing the operation of (3) step is controlled at-10～-5 ℃, and other operational condition is identical with embodiment 4, obtains 2,3-two fluoro-5-bromophenol 141.0g, and molar yield 86%, after measured, purity is 91%.
Embodiment 6
The ehter bond temperature of reaction of taking off of removing the operation of (5) step is controlled at 90～100 ℃, and other operational condition is identical with embodiment 1, obtains 2,3-two fluoro-5-bromophenol 135.0g, and molar yield 82%, after measured, purity is 91%.
Embodiment 7
Step (1):
Undertaken by embodiment 1 identical method, different is to use the sodium methylate of 2.5mol to replace KOH.
Step (2)-(5)
The operational condition of step (2)-(5) obtains 2 with embodiment 1,3-two fluoro-5-bromophenol 290g.Sampling GC assay products content is 95.2%, molar yield: 60.69%.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values are equally at the application's appended claims institute restricted portion.
Claims (14)
1. one kind prepares 2, the method for 3-two fluoro-5-bromophenols, and this method may further comprise the steps:
(1) with 2,3, the 4-trifluoronitrobenzene is a raw material, prepares two fluoro nitro-paraffin oxygen base benzene to be selected from any following mode:
(i) make 2,3,4-trifluoronitrobenzene and alkali-metal alkyl alkoxide carry out substitution reaction, and the alkyl in the described alkyl alkoxide is C
1～C
7Alkyl;
(ii) in the presence of alkali or alkali-metal C
1～C
7Under the existence of alkyl alkoxide, make 2,3,4-trifluoronitrobenzene and alkyl alcohol carry out substitution reaction, and the alkyl in the described alkyl alcohol is C
1～C
7Alkyl;
(2) with reductive agent the two fluoro nitro-paraffin oxygen base benzene that step (1) obtains are reduced into two fluoro alkoxyl anilines; Described reductive agent is to be selected from following one or more: hydrogen, iron powder, zinc powder, lithium aluminum hydride or Raney's nickel;
(3) be difluoro bromo alkoxyl aniline with bromizating agent with the two fluoro alkoxyl aniline brominations that step (2) obtains; Described bromizating agent is Br
2
(4) the difluoro bromo alkoxyl aniline that step (3) is obtained obtains 2,3-two fluoro-5-bromine alkoxy benzenes through diazotization and desamination reaction successively;
(5) step (4) is obtained 2,3-two fluoro-5-bromine alkoxy benzenes obtain 2 after taking off ehter bond, 3-two fluoro-5-bromophenols.
2. the method for claim 1 is characterized in that, described alkali-metal alkyl alkoxide is selected from sodium alkyl alcohol or alkyl potassium alcoholate; And/or
Described alkali is the oxyhydroxide of basic metal or alkaline-earth metal.
3. method as claimed in claim 2 is characterized in that, described alkali is to be selected from one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta, lithium hydroxide.
4. the method for claim 1 is characterized in that, the alkyl in described alkali-metal alkyl alkoxide and the described alkyl alcohol is C
1～C
5Alkyl.
5. the method for claim 1 is characterized in that, the alkyl in described alkali-metal alkyl alkoxide and the described alkyl alcohol is C
1～C
3Alkyl.
6. the method for claim 1 is characterized in that, the temperature of reaction of step (1) is in-20 ℃～150 ℃ scope.
7. the method for claim 1 is characterized in that, the temperature of reaction of step (1) is in 20 ℃～80 ℃ scope.
8. the method for claim 1 is characterized in that, in the step (1), the usage quantity of alkali-metal alkyl alkoxide of reactant or alkyl alcohol is equivalent to 2,3,0.5～5 times of molar weight of 4-trifluoronitrobenzene.
9. the method for claim 1 is characterized in that, the usage quantity of alkali-metal alkyl alkoxide of reactant or alkyl alcohol is equivalent to 2,3,1～2 times of molar weight of 4-trifluoronitrobenzene.
10. the method for claim 1, it is characterized in that, step (1) is carried out in the presence of solvent, solvent for use is to be selected from following one or more: ethanol, sherwood oil, methyl tertiary butyl ether, acetonitrile, toluene, benzene, ethyl acetate, N, dinethylformamide, ethylene dichloride, chloroform or N-Methyl pyrrolidone; And/or
Step (2) is carried out in the presence of solvent, solvent for use is to be selected from following one or more: ethanol, sherwood oil, methyl tertiary butyl ether, acetonitrile, toluene, benzene, ethyl acetate, N, dinethylformamide, ethylene dichloride, chloroform or N-Methyl pyrrolidone.
11. the method for claim 1, it is characterized in that, step (3) is carried out in the presence of solvent, and solvent for use is to be selected from following one or more: ethanol, sherwood oil, acetonitrile, toluene, benzene, ethyl acetate, dimethyl formamide, N-Methyl pyrrolidone.
12. the method for claim 1 is characterized in that, step (5) is carried out in the presence of solvent, and solvent for use is to be selected from following one or more: mercaptan, propylmercaptan, isopropyl mercaptan, dimethyl sulfoxide (DMSO), tetramethylene sulfone, ethylene dichloride.
13. the method for claim 1 is characterized in that, the temperature of reaction of step (2) is in-10 ℃～150 ℃ scope.
14. the method for claim 1 is characterized in that, the temperature of reaction of step (2) is in 30 ℃～90 ℃ scope.
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| CN104649869B (en) * | 2013-11-18 | 2016-07-13 | 江苏扬农化工股份有限公司 | A kind of method that the 2,5-of utilization dichloro 2, 2-Oxydiphenol prepares 2,5-chlorophenesic acid |
| CN103601613B (en) * | 2013-11-19 | 2015-07-08 | 浙江林江化工股份有限公司 | Preparation method of 3, 4, 5-trifluoro bromobenzene |
| CN105085190B (en) * | 2015-08-28 | 2017-01-25 | 中节能万润股份有限公司 | Preparing method of 2,6-difluoro-4-bromophenol |
| CN106478377B (en) * | 2016-08-28 | 2019-10-01 | 浙江林江化工股份有限公司 | A kind of synthetic method of 2,3- Difluoro-5-Bromophenol |
| CN110627646A (en) * | 2019-10-18 | 2019-12-31 | 利尔化学股份有限公司 | Preparation method of 5-fluoro-2-nitrophenol |
| CN112047804B (en) * | 2020-09-10 | 2023-06-27 | 内蒙古永太化学有限公司 | Preparation method of 3, 5-dichloro-4-fluorobromobenzene compound |
| CN112142567B (en) * | 2020-10-12 | 2023-11-14 | 浙江永太科技股份有限公司 | Preparation method of 2-fluoro-3-chlorophenol |
| CN113929582B (en) * | 2021-11-04 | 2024-01-16 | 山东京博农化科技股份有限公司 | Synthesis method of 2- (5-fluoro-2-nitrophenoxy) acetate |
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