CN1948251A - Preparation method of 2,3-difluoro alkoxy benzene - Google Patents
Preparation method of 2,3-difluoro alkoxy benzene Download PDFInfo
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- CN1948251A CN1948251A CN 200610118056 CN200610118056A CN1948251A CN 1948251 A CN1948251 A CN 1948251A CN 200610118056 CN200610118056 CN 200610118056 CN 200610118056 A CN200610118056 A CN 200610118056A CN 1948251 A CN1948251 A CN 1948251A
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Abstract
The present invention relates to a preparation method of 2,3-difluoroalkoxybenzne. It is characterized by that said invention uses 2,3,4-trifluoronitrobenzene as raw material, and makes it successively undergo the processes of substitution, reduction, diazotization and deamination reaction so as to obtain the invention 2,3-difluoroalkoxybenzene.
Description
Technical field
The present invention relates to a kind ofly 2, the preparation method of 3-difluoro alkoxy benzene is specifically related to a kind of C of containing
1～C
102 of alkoxyl group, the preparation method of 3-difluoro alkoxy benzene.
Background technology
2, the 3-difluoro alkoxy benzene is the increasingly extensive intermediate of a kind of purposes, is the intermediate of synthesizing compound of liquid crystal, pharmaceutical compound and the agricultural chemical compound used always.Disclose 2 among the Chinese patent CN89101335, the synthetic method of 3-difluoro alkoxy benzene, the characteristics of this method are to make the deprotonation on the 1-position of adjacent phenyl-difluoride with organometallic reagent, under alkaline condition, handle after making 1-position hydroxylation with electrophilic reagent reaction or oxidation style then with alkylating reagent, obtain corresponding 2, the 3-difluoro alkoxy benzene.The employed most of supplementary material of this method (particularly organometallic reagent) price comparison height, and severe reaction conditions.
Summary of the invention
The purpose of this invention is to provide a kind of 2, the preparation method of 3-difluoro alkoxy benzene, this method technology is simple, reaction conditions is gentle.
The inventive method prepared 2, the 3-difluoro alkoxy benzene is the compound with following structural formula, wherein R is C
1～C
10Alkyl, preferred C
1～C
7Alkyl, more preferably C
1～C
5Alkyl.
The inventive method is with commercial goods 2,3, and the 4-trifluoronitrobenzene is a raw material, and through obtaining 2 behind replacement, reduction, diazotization and the desamination reaction, the 3-difluoro alkoxy benzene may further comprise the steps successively:
(1) is being not less than under-20 ℃ the temperature 2,3, the basic metal that 4-trifluoronitrobenzene and general formula AOR represent or the alkyl alkoxide of alkaline-earth metal carry out substitution reaction and obtain 2, and 3-two fluoro-6-nitro alkoxy benzenes are among its formula of AOR, A is basic metal or alkaline-earth metal, and R is C
1～C
10Alkyl, preferred C
1～C
7Alkyl, more preferably C
1～C
5Alkyl; Or in the presence of alkali, 2,3, the alkyl alcohol that 4-trifluoronitrobenzene and general formula R OH represent carries out substitution reaction and obtains 2,3-two fluoro-6-nitro alkoxy benzenes, wherein R is C
1～C
10Alkyl, preferred C
1～C
7Alkyl, more preferably C
1～C
5Alkyl;
(2) with reductive agent with 2,3-two fluoro-6-nitro alkoxy benzenes are reduced into 2,3-two fluoro-6-aminoalkoxy benzene;
(3) with 2,3-two fluoro-6-aminoalkoxy benzene obtain 2, the 3-difluoro alkoxy benzene through diazotization and desamination reaction successively.
In this application, term " alkyl " expression straight or branched alkyl.Term " alkoxyl group " separately or combining form represent general formula R O, wherein the definition of R is with the definition of aforementioned R.
In the step (1), raw material 2,3, the alkyl alkoxide of 4-trifluoronitrobenzene and reactant alkyl alcohol or basic metal or alkaline-earth metal is the commercial goods.The substitution reaction condition is as follows:
The alkyl alkoxide preferred alkyl sodium alkoxide or the alkyl potassium alcoholate of reactant basic metal or alkaline-earth metal.The alkyl alkoxide of reactant basic metal or alkaline-earth metal or the consumption of alkyl alcohol do not have particular requirement, and the preferred usage quantity of reactant is equivalent to 2,3,0.5～5 times of molar weight of 4-trifluoronitrobenzene, more preferably 1.0～2.0 times of molar weights.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 the low speed of response that influences, 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 etherification reaction, cause that secondary replaces, and the growing amount of increase high boiling product, reduce product yield.Temperature of reaction preferably is no more than 150 ℃, wherein more preferably 20 ℃～80 ℃.Under preferred temperature of reaction, the product yield of substitution reaction can reach more than 90%.
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.
In the step (2):
The reductive mode can be that metal adds acid or hydrogenation catalysis 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 2,1.0～3.5 times of molar weights of 3-two fluoro-6-nitro alkoxy benzenes.
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 preferably water, aqueous ethanolic 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 2,1.0～2.0 times of molar weights of 3-two fluoro-6-nitro alkoxy benzenes.
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) adopts conventional diazotization reaction and desamination reaction operation, and for example in the diazotization reaction, diazo reagent adopts NaNO
2And acid, acid can be adopted hydrochloric acid or sulfuric acid, and 2,3-two fluoro-6-aminoalkoxy benzene are dissolved in the acid salify preferably to carry out about room temperature～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 ℃.
Can directly carry out next step reaction after each step, reaction was finished, but the intermediate product that adopts each step reaction of post processing mode separation and purification such as extraction, suction filtration, washing, drying, precipitation to obtain helps improving the efficient of next step reaction.
The commercialized raw materials of the employed raw material of the inventive method for cheaply being easy to get, it is few to have side reaction, throughput is big, the reaction conditions gentleness, cost is low, easy advantage such as suitability for industrialized production, with preparation method of the present invention obtain 2, the purified back of 3-difluoro alkoxy benzene purity can reach more than 99%, and total recovery can reach about 60%.
Description of drawings
Fig. 1 is 2, the 3-difluoromethoxy phenyl
1The H-NMR spectrogram;
Fig. 2 is 2,3-difluoroethoxy benzene
1The H-NMR spectrogram;
Fig. 3 is 2,3-difluoro propoxy-benzene
1The H-NMR spectrogram;
Fig. 4 is 2,3-difluoro butyl phenyl ether
1The H-NMR spectrogram.
Embodiment
Below in conjunction with embodiment the inventive method is further elaborated, but should understands embodiment not in order to restriction the present 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.
Embodiment 12, the preparation of 3-difluoromethoxy phenyl
The preparation of (1) 2,3-two fluoro-6-nitro anisoles:
In the reaction flask of 500ml, add 31.0g (0.55mol) potassium hydroxide, 250ml toluene, 38.5g (1.2mol) methyl alcohol, at room temperature drip 88.5g (0.5mol) 2 after the mixing, 3, the 4-trifluoronitrobenzene, insulation reaction 1～2 hour 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 2,3-two fluoro-6-nitro anisole 90.8g (0.48mol), molar yield: 96%, after measured, purity is 91%.
The preparation of the amino anisole of (2) 2,3-two fluoro-6-:
In the reaction flask of 500ml, add 83.8g (1.5mol) iron powder, 200ml methyl alcohol and 10ml 30% hydrochloric acid, stir half an hour down at 65 ℃, drip 90.8g (0.48mol) 2,3-two fluoro-6-nitro anisoles, afterreaction was complete in 2 hours, be cooled to room temperature, suction filtration, get filtrate, desolventize back distillation (vacuum tightness 22mmHg, 110 ℃ of top temperature) with the Rotary Evaporators steaming and obtain light yellow liquid 2, the amino anisole 65.2g (0.41mol) of 3-two fluoro-6-, molar yield 85%, after measured, purity is 95.6%.
The preparation of (3) 2,3-difluoromethoxy phenyls:
1) preparation of diazonium salt
Add 110g30% hydrochloric acid in the reaction flask of 500ml, drip 65.2g (0.41mol) 2 in the time of 14 ℃, the amino anisole of 3-two fluoro-6-is warming up to 50 ℃, stirs half an hour, is cooled to-5～0 ℃, drips 20g 10-40%NaNO
2The aqueous solution stirred 30 minutes, and is standby.
2) 2, the preparation of 3-difluoromethoxy phenyl:
In the 500ml reaction flask, add 40.0g (0.38mol) NaH
2PO
2H
2O drips the diazonium liquid that step 1) is produced under 30～50 ℃ of temperature, have bubble to produce, stir 15min, be cooled to-10～10 ℃, get organic layer after the layering of question response liquid, alkali cleaning is washed to neutrality, distillation (vacuum tightness 18mmHg behind anhydrous magnesium sulfate drying, 100 ℃ of top temperature), get colourless transparent liquid 2,3-difluoromethoxy phenyl 46.0g (0.32mol), molar yield 78%, measure through GC, purity is 91.9%.
1H-NMR(CDCl
3，500MHz)δppm：7.02-7.08(m，1H)，6.74-6.89(m，2H)，3.83(s，3H)。
Embodiment 22, the preparation of 3-difluoromethoxy phenyl
The preparation of (1) 2,3-two fluoro-6-nitro anisoles:
In the reaction flask of 500ml, add 38.5g (0.55mol) potassium methylate, 350ml toluene, mix the back and drip 88.5g (0.5mol) 2 down at-15 ℃, 3, the 4-trifluoronitrobenzene, insulation reaction 5～6 hours adds 150ml water again, stir 25min, 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 2,3-two fluoro-6-nitro anisole 63.0g (0.44mol), molar yield: 88%, after measured, purity is 90%.
The preparation of the amino anisole of (2) 2,3-two fluoro-6-:
In the reaction flask of 500ml, add 83.8g (1.5mol) iron powder, 200ml methyl alcohol and 10ml 30% hydrochloric acid, stirred 1 hour down, drip 63.0g (0.44mol) 2 at-5 ℃, 3-two fluoro-6-nitro anisoles, afterreaction was complete in 4 hours, and suction filtration is got filtrate, desolventize back distillation (vacuum tightness 22mmHg with the Rotary Evaporators steaming, 110 ℃ of top temperature) obtain light yellow liquid 2, the amino anisole 60.0g (0.38mol) of 3-two fluoro-6-, molar yield 83.4%, after measured, purity is 96.6%.
The preparation of (3) 2,3-difluoromethoxy phenyls:
1) preparation of diazonium salt
Add 110g30% hydrochloric acid in the reaction flask of 500ml, drip 60.0g (0.38mol) 2 in the time of 14 ℃, the amino anisole of 3-two fluoro-6-is warming up to 50 ℃, stirs half an hour, is cooled to-5～0 ℃, drips 20g 10-40%NaNO
2The aqueous solution stirred 30 minutes, and is standby.
2) 2, the preparation of 3-difluoromethoxy phenyl:
In the 500ml reaction flask, add 40.0g (0.38mol) NaH
2PO
2H
2O drips the diazonium liquid that step 1) is produced under 30～50 ℃ of temperature, have bubble to produce, stir 15min, be cooled to-10～10 ℃, get organic layer after the layering of question response liquid, alkali cleaning is washed to neutrality, distillation (vacuum tightness 18mmHg behind anhydrous magnesium sulfate drying, 100 ℃ of top temperature), get colourless transparent liquid 2,3-difluoromethoxy phenyl 46.0g (0.32mol), molar yield 84%, after measured, purity is 91.9%.
Embodiment 32, the preparation of 3-difluoromethoxy phenyl
The preparation of (1) 2,3-two fluoro-6-nitro anisoles:
In the reaction flask of 500ml, add 31.0g (0.55mol) potassium hydroxide, 250mlDMF, 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 2,3-two fluoro-6-nitro anisole 90.0g (0.47mol), molar yield: 71%, after measured, purity is 83%.
The operational condition of step (2)-(3) obtains colourless transparent liquid 2 with embodiment 1,3-difluoromethoxy phenyl 45.0g (0.31mol), and after measured, purity is 90%
Embodiment 42, the preparation of 3-difluoroethoxy benzene
The preparation of (1) 2,3-two fluoro-6-nitro phenetoles:
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 2,3-two fluoro-6-nitro phenetole 202.0g (0.99mol), molar yield: 99%, after measured, purity is 92%.
The preparation of (2) 2,3-two fluoro-6-amino ethoxy benzene:
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) 2,3-two fluoro-6-nitro phenetoles, about 20min dropwises, and afterreaction was complete in 4 hours, was cooled to room temperature, suction filtration, get filtrate, desolventize back distillation (vacuum tightness 22mmHg, 110 ℃ of top temperature) with the Rotary Evaporators steaming and obtain yellowish brown liquid 2,3-two fluoro-6-amino ethoxy benzene 150.7g (0.87mol), molar yield 88%, after measured, purity is 98.6%.
Method b. in the autoclave of 1000ml with 400ml ethanol and 200.0g (0.985mol) 2,3-two fluoro-6-nitro phenetoles mix, add 5% palladium/carbon catalyst 10g, nitrogen replacement (nitrogen is full of reactor and excessive slightly) back feeds hydrogen, be heated to 40～50 ℃, keep 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) with the Rotary Evaporators steaming, obtain yellowish brown liquid 2,3-two fluoro-6-amino ethoxy benzene 161.0g (0.93mol), molar yield 94%, after measured, purity is 95.6%.
The preparation of (3) 2,3-difluoroethoxy benzene:
1) preparation of diazonium salt
Add 110g30% hydrochloric acid in the reaction flask of 500ml, drip 2 in the time of 14 ℃, 3-two fluoro-6-amino ethoxy benzene 52.0g (0.30mol) are warming up to 55 ℃, stir half an hour, are cooled to-5～0 ℃, drip 40%NaNO
2Aqueous solution 55g stirred 30 minutes, and is standby.
2) 2, the preparation of 3-difluoroethoxy benzene:
In the 1000ml reaction flask, add 38g inferior sodium phosphate and 300g water, under 30～50 ℃ of temperature, drip the diazonium liquid that step 1) is produced, have bubble to produce, drip and stir 15min, be cooled to-10～10 ℃, layering, get organic layer, alkali cleaning is washed to neutrality, distillation (vacuum tightness 25mmHg, 117 ℃ of boiling points) behind anhydrous magnesium sulfate drying gets colourless transparent liquid 2,3-difluoroethoxy benzene 42.7g (0.272mol), molar yield 91%, after measured, purity is 99.5%.
1H-NMR(CDCl
3，500MHz)δppm：7.05-7.13(m，1H)，6.69-6.84(m，2H)，4.03(q，2H)，1.31(t，3H)。
Embodiment 52, the preparation of 3-difluoroethoxy benzene
The preparation of (1) 2,3-two fluoro-6-nitro phenetoles:
In the reaction flask of 1000ml, add 399.7g (4.75mol) potassium ethylate, 550ml toluene, 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 2,3-two fluoro-6-nitro phenetole 200.0g (0.98mol), molar yield: 98%, after measured, purity is 93%.
The preparation of (2) 2,3-two fluoro-6-amino ethoxy benzene:
In the reaction flask of 1000ml, add 168.0g (3mol) iron powder, 400mlDMF and 10ml 30% hydrochloric acid, stir half an hour down at 148 ℃, drip 200.0g (0.98mol) 2,3-two fluoro-6-nitro phenetoles, about 20min dropwises, 4.5 hour afterreaction is complete, be cooled to room temperature, suction filtration is got filtrate, desolventize back distillation (vacuum tightness 22mmHg with the Rotary Evaporators steaming, 110 ℃ of top temperature) obtain yellowish brown liquid 2,3-two fluoro-6-amino ethoxy benzene 146.0g (0.84mol), molar yield 86%, after measured, purity is 92.6%.
The preparation of (3) 2,3-difluoroethoxy benzene:
1) preparation of diazonium salt
Add 110g30% hydrochloric acid in the reaction flask of 500ml, drip 2 in the time of 14 ℃, 3-two fluoro-6-amino ethoxy benzene 52.0g (0.30mol) are warming up to 55 ℃, stir half an hour, are cooled to-5～0 ℃, drip 40%NaNO
2Aqueous solution 55g stirred 30 minutes, and is standby.
2) 2, the preparation of 3-difluoroethoxy benzene:
In the 1000ml reaction flask, add 38g inferior sodium phosphate and 300g water, under 30～50 ℃ of temperature, drip the diazonium liquid that step 1) is produced, have bubble to produce, drip and stir 15min, be cooled to-10～10 ℃, layering, get organic layer, alkali cleaning is washed to neutrality, distillation behind anhydrous magnesium sulfate drying (vacuum tightness 25mmHg, 117 ℃ of top temperature) gets colourless transparent liquid 2,3-difluoroethoxy benzene 42.7g (0.272mol), molar yield 91%, after measured, purity is 99.5%.
Embodiment 62, the preparation of 3-difluoroethoxy benzene
Except that replacing 30% hydrochloric acid with 50% sulfuric acid among (3) the step behaviour, other operational condition is identical with embodiment 4, obtains light yellow liquid 2,3-difluoroethoxy benzene 35.0g (0.223mol), and molar yield 74%, after measured, purity is 89%.
Embodiment 72, the preparation of 3-difluoroethoxy benzene
The temperature of reaction of removing the deaminizating operation of (3) step changes 10 ℃ into, and other operational condition is identical with embodiment 4, obtains light yellow liquid 2,3-difluoroethoxy benzene 38.0g (0.242mol), and molar yield 81%, after measured, purity is 90%.
Embodiment 82, the preparation of 3-difluoro propoxy-benzene
The preparation of (1) 2,3-two fluoro-6-nitro propoxy-benzene:
In the reaction flask of 1000ml, add 59.0g (1.05mol) potassium hydroxide, 550ml toluene, 75.0g (1.25mol) n-propyl alcohol, at room temperature drip 177.0g (1mol) 2 after the mixing, 3, the 4-trifluoronitrobenzene dropwised insulation reaction 1～2 hour, added 300ml water again, stir 15min, organic layer is got in layering, with mixed alkali liquor (10%NaOH/20%NaHCO
3) be washed till neutrality, desolventize through anhydrous magnesium sulfate drying, Rotary Evaporators steaming, obtain reddish-brown liquid 2,3-two fluoro-6-nitro propoxy-benzene 155.1g (0.714mol), molar yield 71.4%, after measured, purity is 96.65%.
The preparation of the amino propoxy-benzene of (2) 2,3-two fluoro-6-:
Method a, in the reaction flask of 1000ml, add 168g (3mol) iron powder, 400ml ethanol and 10ml 30% hydrochloric acid, at 70 ℃ of following agitation and dropping 155.0g (0.71mol) 2,3-two fluoro-6-nitro propoxy-benzene, about 20min dropwises, afterreaction was complete in 4 hours, be cooled to room temperature, suction filtration is got filtrate, desolventize back distillation (vacuum tightness 10mmHg with the Rotary Evaporators steaming, 85 ℃ of top temperature) obtain colourless transparent liquid 2, the amino propoxy-benzene 107.9g (0.55mol) of 3-two fluoro-6-, molar yield 79%, after measured, purity is 98.3%.
With 400ml ethanol and 155.0g (0.71mol) 2,3-two fluoro-6-nitro propoxy-benzene mix method b., add 5% palladium/carbon catalyst 10g, feed hydrogen behind the nitrogen replacement, are heated to 40～50 ℃ in the autoclave of 1000ml, keep 5kgf/cm
2Pressure, afterreaction was complete in 8 hours, was cooled to room temperature, filtered, get filtrate, desolventize back distillation (vacuum tightness 20mmHg, 95 ℃ of top temperature) with the Rotary Evaporators steaming, obtain colourless transparent liquid 2, the amino propoxy-benzene 140.1g (0.75mol) of 3-two fluoro-6-, molar yield 82%, after measured, purity is 99.7%.
The preparation of (3) 2,3-difluoro propoxy-benzene:
1) preparation of diazonium salt
Add 110g30% hydrochloric acid in the reaction flask of 500ml, drip 2 in the time of 14 ℃, the amino propoxy-benzene 52.0g (0.28mol) of 3-two fluoro-6-is warming up to 55 ℃, stirs half an hour, is cooled to-5～0 ℃, drips 40%NaNO
2Aqueous solution 55g stirred 30 minutes, and is standby.
2) 2, the preparation of 3-difluoro propoxy-benzene:
In the 1000ml reaction flask, add 38g inferior sodium phosphate and 300g water, under 30～50 ℃ of temperature, drip the diazonium liquid that step 1) is produced, have bubble to produce, stir 15min, be cooled to-10～10 ℃, layering, get organic layer, alkali cleaning is washed to neutrality, distillation behind anhydrous magnesium sulfate drying (vacuum tightness 40mmHg, 105 ℃ of top temperature) gets weak yellow liquid 2,3-difluoro propoxy-benzene 39.0g (0.23mol), yield 82%, after measured, purity is 99.61%.
1H-NMR(CDCl
3，500MHz)δppm：7.05-7.15(m，1H)，6.70-6.81(m，2H)，4.05(t，2H)，1.62-1.75(m，2H)，0.96(t，3H)。
Embodiment 92, the preparation of 3-difluoro propoxy-benzene
Remove propyl alcohol and 2,3 in the operation of (1) step, the mol ratio of 4-trifluoronitrobenzene is 1.3: 1, other operational condition is identical with embodiment 8, obtains light yellow liquid 2,3-difluoro propoxy-benzene 45.0g (0.263mol), 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 93%, yield 82%.
Embodiment 10 2, the preparation of 3-difluoro propoxy-benzene
The diazotization reaction temperature of removing the operation of (3) step is controlled at-10～-5 ℃, and other operational condition is identical with embodiment 5, obtains light yellow liquid 2,3-difluoro propoxy-benzene 41.0g (0.24mol), and molar yield 86%, after measured, purity is 89%.
Embodiment 11 2, the preparation of 3-difluoro butyl phenyl ether
The preparation of (1) 2,3-two fluoro-6-nitro butyl phenyl ethers:
In the reaction flask of 1000ml, add 42.0g (1.05mol) sodium hydroxide, 550ml toluene, 93.0g (1.25mol) propyl carbinol, at room temperature drip 177.0g (1mol) 2 after the mixing, 3, the 4-trifluoronitrobenzene dropwises, insulation reaction 1～2 hour, add 300ml water again, stir 15min, layering, get organic layer, with mixed alkali liquor (10%NaOH/20%NaHCO
3) be washed till neutrality, desolventize through anhydrous magnesium sulfate drying, Rotary Evaporators steaming, obtain reddish-brown liquid 2,3-two fluoro-6-nitro butyl phenyl ether 211.8g (0.916mol), yield 91.6%, after measured, purity is 95.3%.
The preparation of the amino butyl phenyl ether of (2) 2,3-two fluoro-6-:
Method a, in the reaction flask of 1000ml, add 168.0g (3mol) iron powder, 400ml ethanol and 10ml 30% hydrochloric acid, at 70 ℃ of following agitation and dropping 211.8g (0.916mol) 2,3-two fluoro-6-nitro butyl phenyl ethers, about 20min dropwises, afterreaction was complete in 4 hours, be cooled to room temperature, suction filtration is got filtrate, desolventize back distillation (vacuum tightness 22mmHg with the Rotary Evaporators steaming, 95 ℃ of top temperature) obtain yellow liquid 2, the amino butyl phenyl ether 175.0g (0.87mol) of 3-two fluoro-6-, molar yield 95%, after measured, purity is 98.1%.
With 400ml ethanol and 200g (0.87mol) 2,3-two fluoro-6-nitro butyl phenyl ethers mix method b., add 5% palladium/carbon catalyst 10g, feed hydrogen behind the nitrogen replacement, are heated to 40～50 ℃ in the autoclave of 1000ml, keep 5kgf/cm
2Pressure, afterreaction was complete in 8 hours, was cooled to room temperature, filtered, get filtrate, desolventize back distillation (vacuum tightness 21mmHg, 105 ℃ of top temperature) with the Rotary Evaporators steaming and obtain yellow liquid 2,3-two fluoro-6-amino butyl phenyl ether 138.9g (0.69mol), molar yield 80%, after measured, purity is 89%.
The preparation of (3) 2,3-difluoro butyl phenyl ethers:
1) preparation of diazonium salt
Add 110g30% hydrochloric acid in the reaction flask of 500ml, drip 2 in the time of 14 ℃, the amino butyl phenyl ether 52.0g (0.26mol) of 3-two fluoro-6-is warming up to 55 ℃, stirs half an hour, is cooled to-5～0 ℃, drips 40%NaNO
2Aqueous solution 55g stirred 30 minutes, and is standby.
2) 2, the preparation of 3-difluoro butyl phenyl ether:
In the 1000ml reaction flask, add 38g inferior sodium phosphate and 300g water, under 30～50 ℃ of temperature, drip the diazonium liquid that step 1) is produced, have bubble to produce, stir 15min, be cooled to-10～10 ℃, layering, get organic layer, alkali cleaning is washed to neutrality, through anhydrous magnesium sulfate drying, distillation (115 ℃ of top temperature, vacuum tightness 39mmHg), get colourless transparent liquid 2,3-difluoro butyl phenyl ether 47.0g (0.25mol), molar yield 96%, after measured, purity is 72.4%.
1H-NMR(CDCl
3，500MHz)δppm：7.05-7.15(m，1H)，6.70-6.85(m，2H)，4.03(t，2H)，1.71-1.87(m，2H)，1.40-1.52(m，2H)，0.92(t，3H)。
Embodiment 12 2, the preparation of 3-difluoro butyl phenyl ether
The alkaline matter that removes in the operation of (1) step adopts potassium hydroxide, and other operational condition is identical with embodiment 11, obtains colourless transparent liquid 2,3-difluoro butyl phenyl ether 36.0g (0.19mol), and molar yield 74%, after measured, purity is 76%.The yield 94% of (1) step operation.
Embodiment 13 2, the preparation of 3-difluoro butyl phenyl ether
The diazotization reaction temperature of removing the operation of (3) step is controlled at-10～-5 ℃, and other operational condition is identical with embodiment 11, obtains yellow liquid 2,3-difluoro butyl phenyl ether 44.9g (0.24mol), and molar yield 91%, after measured, purity is 86%.
Embodiment 14 2, the preparation of 3-difluoro amyl phenyl ether
The preparation of (1) 2,3-two fluoro-6-nitro amyl phenyl ethers:
In the reaction flask of 1000ml, add 42.0g (1.05mol) sodium hydroxide, 570ml toluene, 101.3g (1.15mol) amylalcohol, at room temperature drip 177.0g (1mol) 2 after the mixing, 3, the 4-trifluoronitrobenzene dropwises, insulation reaction 1～2 hour, add 320ml water again, stir 15min, layering, get organic layer, with mixed alkali liquor (10%NaOH/20%NaHCO
3) be washed till neutrality, desolventize through anhydrous magnesium sulfate drying, Rotary Evaporators steaming, obtain yellow liquid 2,3-two fluoro-6-nitro amyl phenyl ether 212.0g (0.86mol), molar yield 86%, after measured, purity 92.7%.
The preparation of the amino amyl phenyl ether of (2) 2,3-two fluoro-6-:
Method a, in the reaction flask of 1000ml, add 168g (3mol) iron powder, 420ml amylalcohol and 15ml 30% hydrochloric acid, at 75 ℃ of following agitation and dropping 212.0g (0.86mol) 2,3-two fluoro-6-nitro amyl phenyl ethers, about 15min dropwises, afterreaction was complete in 3 hours, be cooled to room temperature, suction filtration is got filtrate, desolventize back distillation (100 ℃ of top temperature with the Rotary Evaporators steaming, vacuum tightness 38mmHg) obtains colourless transparent liquid 2, the amino amyl phenyl ether 150.7g (0.70mol) of 3-two fluoro-6-, molar yield 81%, after measured, purity is 96.6%.
Method b. in the autoclave of 1000ml with 400ml Pentyl alcohol and 200.0g (0.82mol) 2,3-two fluoro-6-nitro amyl phenyl ethers mix, and add 5% palladium/carbon catalyst 15g, and nitrogen (being full of reactor and excessive slightly) displacement back feeds hydrogen, be heated to 40～50 ℃, keep 5kgf/cm
2Pressure, afterreaction was complete in 6 hours, be cooled to room temperature, filter, get filtrate, desolventize back distillation (100 ℃ of top temperature with the Rotary Evaporators steaming, vacuum tightness 38mmHg) obtains colourless transparent liquid 2, the amino amyl phenyl ether 170.0g (0.79mol) of 3-two fluoro-6-, molar yield 96%, after measured, purity is 96.6%.
The preparation of (3) 2,3-difluoro amyl phenyl ethers:
1) preparation of diazonium salt
Add 150g30% hydrochloric acid in the reaction flask of 500ml, drip 2 in the time of 14 ℃, the amino amyl phenyl ether 56.0g (0.26mol) of 3-two fluoro-6-is warming up to 65 ℃, stirs half an hour, is cooled to-5～0 ℃, drips 40%NaNO
2Aqueous solution 55g stirred 30 minutes, and is standby.
2) 2, the preparation of 3-difluoro amyl phenyl ether:
In the 1000ml reaction flask, add 41g inferior sodium phosphate and 350g water, under 30～50 ℃ of temperature, drip the diazonium liquid that step 1) is produced, have bubble to produce, stir 15min, be cooled to-10～10 ℃, layering, get organic layer, alkali cleaning is washed to neutrality, distillation behind anhydrous magnesium sulfate drying (110 ℃ of top temperature, vacuum tightness 34mmHg) gets colourless transparent liquid 2,3-difluoro amyl phenyl ether 48.0g (0.24mol), molar yield 92% is measured through GC, and purity is 99.5%.
Claims (13)
1. one kind 2, the preparation method of 3-difluoro alkoxy benzene, said 2, the 3-difluoro alkoxy benzene is a structural formula
The compound of expression, wherein R is C
1～C
10Alkyl is characterized in that, said method comprising the steps of:
(1) is being not less than under-20 ℃ the temperature 2,3, the basic metal that 4-trifluoronitrobenzene and general formula AOR represent or the alkyl alkoxide of alkaline-earth metal carry out substitution reaction and obtain 2, and 3-two fluoro-6-nitro alkoxy benzenes are among its formula of AOR, A is basic metal or alkaline-earth metal, and R is C
1～C
10Alkyl; Or in the presence of alkali, 2,3, the alkyl alcohol that 4-trifluoronitrobenzene and general formula R OH represent carries out substitution reaction and obtains 2,3-two fluoro-6-nitro alkoxy benzenes, wherein R is C
1～C
10Alkyl;
(2) with reductive agent with 2,3-two fluoro-6-nitro alkoxy benzenes are reduced into 2,3-two fluoro-6-aminoalkoxy benzene;
(3) 2,3-two fluoro-6-aminoalkoxy benzene obtain 2, the 3-difluoro alkoxy benzene through diazotization and desamination reaction successively.
2. according to claim 12, the preparation method of 3-difluoro alkoxy benzene, the alkyl alkoxide that it is characterized in that basic metal or alkaline-earth metal is sodium alkyl alcohol or alkyl potassium alcoholate.
3. according to claim 12, the preparation method of 3-difluoro alkoxy benzene is characterized in that R is C
1～C
5Alkyl.
4. according to claim 1 or 3 described 2, the preparation method of 3-difluoro alkoxy benzene is characterized in that described alkali is sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta, lithium hydroxide, sodium alkyl alcohol or alkyl potassium alcoholate.
5. according to claim 1 or 2 or 3 described 2, the preparation method of 3-difluoro alkoxy benzene is characterized in that the temperature of reaction of step (1) is-20 ℃～150 ℃.
6. according to claim 52, the preparation method of 3-difluoro alkoxy benzene is characterized in that described temperature of reaction is 20 ℃～80 ℃.
7. according to claim 1 or 2 or 3 described 2, the preparation method of 3-difluoro alkoxy benzene is characterized in that 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.
8. according to claim 72, the preparation method of 3-difluoro alkoxy benzene is characterized in that 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.
9. according to claim 1 or 2 or 3 described 2, the preparation method of 3-difluoro alkoxy benzene is characterized in that step (1) use ethanol, sherwood oil, acetonitrile, toluene, benzene, ethyl acetate, dimethyl formamide, ethylene dichloride, chloroform or N-Methyl pyrrolidone are as solvent.
10. according to claim 1 or 2 or 3 described 2, the preparation method of 3-difluoro alkoxy benzene is characterized in that described reductive agent is hydrogen, iron powder, zinc powder, lithium aluminum hydride or Raney's nickel.
11. according to claim 1 or 2 or 3 described 2, the preparation method of 3-difluoro alkoxy benzene is characterized in that the temperature of reaction of step (2) is-10 ℃～150 ℃.
12. according to claim 11 2, the preparation method of 3-difluoro alkoxy benzene is characterized in that described temperature of reaction is 30 ℃～90 ℃.
13. according to claim 1 or 2 or 3 described 2, the preparation method of 3-difluoro alkoxy benzene is characterized in that step (2) makes water, aqueous ethanolic solution, ethanol, sherwood oil, acetonitrile, toluene, benzene, ethyl acetate, dimethyl formamide, ethylene dichloride, chloroform or N-Methyl pyrrolidone as solvent.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584546A (en) * | 2011-09-26 | 2012-07-18 | 盘锦兴福化工有限公司 | Synthesis method of 2,3-difluorobenzene ester |
| CN102603496A (en) * | 2011-09-26 | 2012-07-25 | 盘锦兴福化工有限公司 | Method for synthesizing 1-butoxy-2,3-difluorobenzene |
| CN102617303A (en) * | 2012-02-20 | 2012-08-01 | 石家庄诚志永华显示材料有限公司 | Multi-fluorine substituted bi-(phenyl acetenyl) benzene derivative, preparation method thereof and application |
| CN108250051A (en) * | 2018-01-12 | 2018-07-06 | 浙江鼎龙科技有限公司 | The preparation method of 2,3- difluoro ethers |
| CN114835562A (en) * | 2022-06-27 | 2022-08-02 | 山东华安新材料有限公司 | Preparation method of methoxyflurane |
-
2006
- 2006-11-08 CN CN 200610118056 patent/CN1948251A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584546A (en) * | 2011-09-26 | 2012-07-18 | 盘锦兴福化工有限公司 | Synthesis method of 2,3-difluorobenzene ester |
| CN102603496A (en) * | 2011-09-26 | 2012-07-25 | 盘锦兴福化工有限公司 | Method for synthesizing 1-butoxy-2,3-difluorobenzene |
| CN102617303A (en) * | 2012-02-20 | 2012-08-01 | 石家庄诚志永华显示材料有限公司 | Multi-fluorine substituted bi-(phenyl acetenyl) benzene derivative, preparation method thereof and application |
| CN108250051A (en) * | 2018-01-12 | 2018-07-06 | 浙江鼎龙科技有限公司 | The preparation method of 2,3- difluoro ethers |
| CN114835562A (en) * | 2022-06-27 | 2022-08-02 | 山东华安新材料有限公司 | Preparation method of methoxyflurane |
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