CN101445460B - Method for preparing 2-fluoride-5-alkoxyl aniline - Google Patents
Method for preparing 2-fluoride-5-alkoxyl aniline Download PDFInfo
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- CN101445460B CN101445460B CN2008102052221A CN200810205222A CN101445460B CN 101445460 B CN101445460 B CN 101445460B CN 2008102052221 A CN2008102052221 A CN 2008102052221A CN 200810205222 A CN200810205222 A CN 200810205222A CN 101445460 B CN101445460 B CN 101445460B
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Abstract
The invention relates to a method for preparing 2-fluoride-5-alkoxyl aniline. In the method, 2-nitrobenzene is used as raw material for preparing the 2-fluoride-5-alkoxyl aniline by substitution reaction, reduction reaction and etherification reaction. The invention has the advantages of short synthesis route, mild condition, easy industrialization realization, etc. An obtained target product has high purity and stable quality and meets the requirement of being used as an intermediate product completely.
Description
Technical field
The present invention relates to a kind of preparation method of 2-fluoro-5-alkoxyl aniline, be specifically related to a kind of C of containing
1-C
10The preparation method of the 2-fluoro-5-alkoxyl aniline of alkoxyl group.
Background technology
2-fluoro-5-alkoxyl aniline is the increasingly extensive intermediate of a kind of purposes, is the intermediate of synthetic pharmaceutical compound, agricultural chemical compound and the electronic chemical product used always.
In the prior art, generally be to make the deprotonation on the 5-position of adjacent fluoroaniline, react with electrophilic reagent then with organometallic reagent, perhaps, make 5-position hydroxylation, then under alkaline condition by oxidation style, handle with alkylating reagent, obtain corresponding 2-fluoro-5-alkoxyl aniline.
But the employed most of supplementary material of this method (particularly organometallic reagent) price comparison costliness, and severe reaction conditions.
U.S. Pat 4,006 discloses a kind of preparation method of 2-fluoro-5-anisidine in 185, with meta-methoxy oil of mirbane is raw material, react with catalyzer and anhydrous hydrogen fluoride under 42.5atm pressure, single step reaction makes 2-fluoro-5-anisidine, yield 29.4%.Though this method step is not long, used fluorination reagent HF is high carcinogenic high toxicity compound, is not suitable for large-scale industrial production, and this method need carry out under higher pressure, has also buried bigger potential safety hazard.
Therefore, wish a kind of method for preparing 2-fluoro-5-alkoxyl aniline of exploitation in this area, wherein used supplementary material is cheap, and reaction conditions is simply gentle.
The present inventor finds with the 2-fluoronitrobenzene to be raw material through a large amount of research, successively by replacement, reduction and etherification reaction, can obtain 2-fluoro-5-alkoxyl aniline.This method technology is simple, reaction conditions is gentle.On the basis of above-mentioned discovery, finished the present invention.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method of 2-fluoro-5-alkoxyl aniline, this method technology is simple, reaction conditions is gentle.
Method of the present invention is used to prepare the 2-fluoro-5-alkoxyl aniline with following structural formula, and wherein R is C
1-C
10Straight or branched alkyl, perhaps C
1-C
7Straight or branched alkyl, perhaps C
1-C
5The straight or branched alkyl.
Preparation method of the present invention is to be raw material with commercial goods 2-fluoro-oil of mirbane, replaces successively, reduction and etherification reaction, obtains 2-fluoro-5-alkoxyl aniline, said method comprising the steps of:
(1) be not less than in temperature under-10 ℃ the condition, 2-fluoronitrobenzene and bromizating agent reaction generate 2-fluoro-5-bromo nitrobenzene.
(2) with the 2-fluoro-5-bromo nitrobenzene reaction that obtains in reductive agent and the step (1), 2-fluoro-5-bromo nitrobenzene is reduced into 2-fluoro-5-bromaniline.
(3) be not less than under 60 ℃ the temperature, in the presence of catalyzer, the basic metal that 2-fluoro-5-bromaniline and general formula AOR represent or the alkyl alkoxide of alkaline-earth metal carry out the etherificate substitution reaction and obtain 2-fluoro-5-alkoxyl aniline, among its formula of AOR, A is basic metal or alkaline-earth metal, and R is C
1-C
10The straight or branched alkyl, preferred C
1-C
7Straight or branched alkyl, more preferably C
1-C
5The straight or branched alkyl; Perhaps in the presence of alkali, the alkyl alcohol that 2-fluoro-5-bromaniline and general formula R OH represent carries out substitution reaction and obtains 2-fluoro-5-alkoxyl aniline, and wherein R is C
1-C
10The straight or branched alkyl, preferred C
1-C
7Straight or branched alkyl, more preferably C
1-C
5The straight or branched alkyl.
In the above-mentioned steps (1), raw material 2-fluoronitrobenzene and bromizating agent can be the commercial goods, and also available any currently known methods makes.The bromination substitution reaction is following to be carried out: raw material 2-fluoronitrobenzene is added dense H
2SO
4In, slowly adding bromizating agent then, temperature is at-10 ℃-50 ℃, preferred 0 ℃-20 ℃.
Used bromizating agent is this area used bromizating agent usually, is preferably bromine, C5H6Br2N2O2, NBS (N-bromo-succinimide), HBr (hydrogen bromide).
The consumption that is preferably the alkyl alkoxide of described basic metal or alkaline-earth metal or alkyl alcohol is equivalent to 2-10 times of molar weight of 2-fluoronitrobenzene, be that the alkyl alkoxide of basic metal or alkaline-earth metal or the mol ratio of alkyl alcohol consumption and 2-fluoronitrobenzene consumption are 2: 1-10: 1, being preferably described mol ratio is 3: 1-5: 1.
The consumption that is preferably described bromizating agent is equivalent to 0.5-2 times of molar weight of 2-fluoronitrobenzene, and promptly the mol ratio of bromizating agent consumption and 2-fluoronitrobenzene consumption is 0.5: 1-2: 1.
Can adopt ordinary method (as GC etc.) that the performance level of reaction is carried out tracking monitor.
In the above-mentioned steps (2), the reductive mode can be that metal adds acid or hydrogenating reduction method.
Available metallic reducing agent includes but not limited to iron powder, zinc powder, lithium aluminum hydride or Raney's nickel, wherein
Described 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 or 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 weight of 2-fluoro-5-bromo nitrobenzene, and promptly the mol ratio of reductive agent consumption and 2-fluoro-5-bromo nitrobenzene consumption is 1: 1-3.5: 1.
Described being reflected in the solvent carried out, can use any solvent that reaction is had no adverse effects, as alcohols, ethers, nitrile, aromatics, ester class or aprotic polar solvent, wherein preferably water, aqueous ethanolic solution, ethanol, sherwood oil, acetonitrile, toluene, ethyl acetate or DMF, more preferably aqueous ethanolic solution.
Consumption to solvent does not have particular restriction, only otherwise stable the getting final product of influence reaction.Preferably solvent load is a 10-20 times of molar weight of 2-fluoro-5-bromo nitrobenzene, and promptly the mol ratio of solvent consumption and 2-fluoro-5-bromo nitrobenzene consumption is 10: 1-20: 1.
Temperature of reaction is not had particular restriction, and preferably temperature of reaction is-10 ℃-150 ℃, and more preferably temperature of reaction is 30 ℃-90 ℃.Under preferred temperature, can obtain higher reaction efficiency, the product yield of reduction reaction can reach about 90%.
Can adopt ordinary method (as GC etc.) that the performance level of reaction is carried out tracking monitor.
Reaction times is depended on temperature of reaction, solvent and concrete reactant, generally can finish reaction about 1-8 hour.
In step (3), carry out the etherificate substitution reaction.Used basic metal or native alkali-metal alkyl alkoxide preferred alkyl sodium alkoxide or alkyl potassium alcoholate in the step (3).
The consumption of basic metal or native alkali-metal alkyl alkoxide generally is equivalent to 1-5 times of molar weight of 2-fluoro-5-bromaniline, the mol ratio that is basic metal or native alkali-metal alkyl alkoxide consumption and 2-fluoro-5-bromo nitrobenzene amine consumption is 1: 1-5: 1, preferred 2-3 times of molar weight, promptly the mol ratio of preferred as alkali or native alkali-metal alkyl alkoxide consumption and 2-fluoro-5-bromo nitrobenzene amine consumption is 2: 1-3: 1.Under above-mentioned consumption, can improve the reaction efficiency of initial compounds 2-fluoro-5-bromaniline, convenient later processing operation.
Used catalyzer is preferably and contains Cu in the reaction of step (3)
2+Catalyzer, preferably CuI, CuCl, CuBr or CuCN, more preferably CuI.
The consumption of reacting middle catalyst is equivalent to 0.05-0.2 times of molar weight of 2-fluoro-5-bromaniline, the mol ratio that is catalyst levels and 2-fluoro-5-bromaniline consumption is 0.05: 1-0.2: 1, preferred 0.05: 1-0.1: 1 times of molar weight, promptly the mol ratio of preferred catalyst consumption and 2-fluoro-5-bromaniline consumption is 0.05: 1-0.1: 1.
Reaction temperature is spent to hang down influences speed of response, and when temperature was lower than 60 ℃, substitution reaction was normally carried out than difficulty, improve temperature of reaction energy fast reaction speed, but the too high selectivity that can influence etherification reaction of temperature causes that secondary replaces, and the growing amount of increase high boiling product, reduce product yield.Therefore, be preferably 60 ℃-120 ℃ of temperature of reaction, be more preferably 80 ℃-100 ℃.Under preferred temperature of reaction, the product yield of substitution reaction can reach 95%.
Used alkali is organic bases or mineral alkali in the step (3), and organic bases can be the alkyl alkoxide of basic metal or alkaline-earth metal, preferred alkyl sodium alkoxide or alkyl potassium alcoholate; The oxyhydroxide of mineral alkali preferred as alkali or alkaline-earth metal is preferably hydrated barta, sodium hydroxide or potassium hydroxide, is more preferably hydrated barta.
Etherification reaction carries out in solvent, can use any solvent that reaction is had no adverse effects, as alcohols, ethers, nitrile, aromatic compound, ester class, halohydrocarbon or aprotic polar solvent, wherein be preferably ethanol, methyl alcohol, toluene, DMF or ethylene dichloride, be more preferably methyl alcohol.Solvent there is not particular requirement, only otherwise stable the getting final product of influence reaction.Preferred solvent load is a 4-8 times of molar weight of 2-fluoro-5-bromaniline, and promptly the mol ratio of solvent consumption and 2-fluoro-5-bromaniline consumption is 4: 1-8: 1.
Target product 2-fluoro-5-alkoxyl aniline can adopt methods such as ebulliometry, gaseous mass spectrum, inspection mr to detect proof.
Can directly carry out next step reaction after each reaction is finished, 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 helps improving the efficient of next step reaction.
The commercialized raw materials of the employed raw material of method of the present invention for cheaply being easy to get, have that side reaction is few, throughput is big, reaction conditions is gentle, cost is low and advantage such as easy suitability for industrialized production, after the 2-fluoro-5-alkoxyl aniline that obtains with method of the present invention is purified, purity can reach more than 99%, and total recovery can reach more than 60%.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only are used to illustrate the present invention, rather than limitation of the scope of the invention.The experimental technique of unreceipted actual conditions in the following example according to normal condition, or carries out according to the condition that manufacturer advises.Unless otherwise indicated, otherwise all umbers are molar part, and all per-cents are weight percentage.
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.
Testing method
1. follow the tracks of the detection reaction performance level
The detection of reacting finisheding degree is finished with the GC method.Concrete grammar is:
Vapor-phase chromatography or liquid phase chromatography are adopted in each degree of purity of production analysis, and vapor-phase chromatography adopts GC-14C type gas chromatograph (Tianjin, island company) to measure, and chromatographic column is the SPB-5 post; Hydrogen flame detector, column temperature adopts temperature programming: the fs initial temperature (℃): 100, the initial temperature hold-time (min): 2, temperature rise rate (℃/min): 20, final temperature (℃): 280, the eventually warm hold-time (min): 6.5; Carrier gas is a nitrogen, and carrier gas flux is 0.01MPa, split stream injector,, and 1/10 of splitting ratio: P=6MPa, sample size are 0.1ul.Adopting area normalization method to calculate measures.
2. the detection of target product is confirmed
Detection to target product is to carry out with ordinary methods such as ebulliometry, gaseous mass spectrum or nucleus magnetic resonance.
3 measure the purity of product
The mensuration of product purity is carried out in accordance with the following methods.
Vapor-phase chromatography or liquid phase chromatography are adopted in each degree of purity of production analysis, and vapor-phase chromatography adopts GC-14C type gas chromatograph (Tianjin, island company) to measure, and chromatographic column is the SPB-5 post; Hydrogen flame detector, column temperature adopts temperature programming: the fs initial temperature (℃): 100, the initial temperature hold-time (min): 2, temperature rise rate (℃/min): 20, final temperature (℃): 280, the eventually warm hold-time (min): 6.5; Carrier gas is a nitrogen, and carrier gas flux is 0.01MPa, split stream injector,, and 1/10 of splitting ratio: P=6MPa, sample size are 0.1ul.Adopt area normalization method to calculate and measure, liquid chromatography adopts Agilent1200 type hplc determination, and chromatographic column is the vp-ods post, 4.6*150mm, 5um, moving phase: 60%0.05MKH
2PO
4: 40%ACN, flow velocity: 1ml/min, detector: 254nm, 25 ℃ of temperature adopt area normalization method to calculate and measure.
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 defined or explanation, same meanings of being familiar with of all specialties used herein and scientific words and those skilled in the art.Any in addition method similar or impartial to described content and material all can be applicable in the inventive method.
Below respectively three-step reaction is elaborated.
Embodiment 1
(1) preparation of 2-fluoro-5-bromo nitrobenzene
O-fluoronitrobenzene 141 grams (1mol) and the vitriol oil 200 grams are added in the 500ml four-hole bottle, under cryosel is bathed, are cooled to 0-10 ℃, slowly add C5H6Br2N2O2 132 grams in batches, maintain the temperature at 0-10 ℃.After adding, its temperature is slowly gone up to 25 ℃ of room temperatures, track to material content less than 1% with GC simultaneously, pour in the frozen water, add the extraction of 200ml ethylene dichloride, separatory, washing, drying, precipitation obtains 2-fluoro-5-bromo nitrobenzene 146.5 grams (0.67mol), purity 98.16%, yield 67%.
(2) preparation of 2-fluoro-5-bromaniline
With 336 gram water, 112 gram Fe powder add in the 1L four-hole bottles, add 12ml 30% dense HCl, are warming up to 80 ℃ of activation, treat to have on bottle wall golden yellow solid to occur being activated, slowly splash into the 2-fluoro-5-bromo nitrobenzene that obtains in above-mentioned (1), drip off in 1 hour.Continue reaction 30 minutes, track to material content less than 1% with GC, stopped reaction.Filter, separatory, washing, drying, precipitation, weighing obtains 2-fluoro-5-bromaniline 108.6 grams (0.57mol), purity 95%, feed stock conversion is 100%, productive rate is 85.3%.
(3) preparation of 2-fluoro-5-anisidine
CuI 2 grams are added in the 250ml four-hole bottle, at N
2Protection adds 2-fluoro-5-bromaniline 20 grams (0.11mol) that obtain in above-mentioned (2), CH down
3ONa (30%) 96 gram is heated to 90 ℃, tracks to material content less than 1% with GC, filter, and washing, precipitation, drying, weighing obtains 2-fluoro-5-anisidine 15.5 grams (0.11mol), purity 97.56%, transformation efficiency is 100%, productive rate 100%.
Embodiment 2
(1) preparation of 2-fluoro-5-bromo nitrobenzene
With o-fluoronitrobenzene 141 grams (1mol), the vitriol oil 200 grams are added in the 500ml four-hole bottle, under cryosel is bathed, be cooled to-10 ℃, slowly add bromine 132 grams in batches, maintain the temperature at-10 ℃, after adding, its temperature slowly can be got back to room temperature (25 ℃), GC tracks to raw material less than 1% simultaneously, pour in the frozen water, add the extraction of 200ml ethylene dichloride, separatory, washing, drying, precipitation, get 2-fluoro-5-bromo nitrobenzene 145.8 grams (0.66mol), purity 97.19%, yield 66%.
(2) preparation of 2-fluoro-5-bromaniline
With 336 gram water, 112 gram Fe powder add in the 1L four-hole bottles, add 12ml 30% dense HCl, are warming up to 95 ℃ of activation, treat to have on bottle wall golden yellow solid to occur being activated, slowly splash into the 2-fluoro-5-bromo nitrobenzene that obtains in above-mentioned (1), drip off in 1 hour.Continue reaction 30 minutes, track to material content less than 1% with GC, stopped reaction.Filter, separatory, washing, drying, precipitation, weighing obtains 2-fluoro-5-bromaniline 100 grams (0.53mol), purity 90%, feed stock conversion is 100%, productive rate is 80.2%.
(3) preparation of 2-fluoro-5-anisidine
The CuI2 gram is added in the 250ml four-hole bottle, at N
2Protection adds 2-fluoro-5-bromaniline 20 grams (0.11mol) that obtain in above-mentioned (2), CH down
3ONa (30%) 96 gram is heated to 100 ℃, and GC tracks to material content less than 1%.Filter, washing, precipitation, drying, weighing obtains 2-fluoro-5-anisidine 15.5 grams, purity 95.52%, transformation efficiency is 100%, productive rate 100%.
Embodiment 3
(1) preparation of 2-fluoro-5-bromo nitrobenzene
O-fluoronitrobenzene 141 grams (1mol) and the vitriol oil 200 grams are added in the 500ml four-hole bottle, are cooled to-10 ℃, slowly add N-bromo-succinimide 132 grams in batches, maintain the temperature at-10 ℃.After adding, its temperature is slowly gone up to 50 ℃, track to material content less than 1% with GC simultaneously, pour in the frozen water, add the extraction of 200ml ethylene dichloride, separatory, washing, drying, precipitation obtains 2-fluoro-5-bromo nitrobenzene 144 grams (0.65mol), purity 92.46%, yield 65.4%.
(2) preparation of 2-fluoro-5-bromaniline
With 336 gram aqueous ethanolic solutions, 112 gram zinc powders add in the 1L four-hole bottle, add the dense HCl of 12ml30%, be warming up to 150 ℃ of activation, treat to have on bottle wall golden yellow solid to occur being activated, slowly splash into the 2-fluoro-5-bromo nitrobenzene that obtains in above-mentioned (1), dripped off in 1 hour.Continue reaction 30 minutes, track to material content less than 1% with GC, stopped reaction.Filter, separatory, washing, drying, precipitation, weighing obtains 2-fluoro-5-bromaniline 101 grams (0.53mol), purity 92%, feed stock conversion is 100%, productive rate is 79.8%.
(3) preparation of 2-fluoro-5-anisidine
The CuCl2 gram is added in the 250ml four-hole bottle, at N
2Protection adds 2-fluoro-5-bromaniline 20 grams (0.11mol) that obtain in above-mentioned (2), CH down
3OKa (30%) 96 gram is heated to 60 ℃, tracks to material content less than 1% with GC, filter, and washing, precipitation, drying, weighing obtains 2-fluoro-5-anisidine 15.5 grams (0.11mol), purity 91.56%, transformation efficiency is 100%, productive rate 100%.
Embodiment 4
(1) preparation of 2-fluoro-5-bromo nitrobenzene
O-fluoronitrobenzene 141 grams (1mol) and the vitriol oil 200 grams are added in the 500ml four-hole bottle, are cooled to-5 ℃, slowly add HBr (hydrogen bromide) 132 grams in batches, maintain the temperature at-10 ℃.After adding, its temperature is slowly gone up to 30 ℃, track to material content less than 1% with GC simultaneously, pour in the frozen water, add the extraction of 200ml ethylene dichloride, separatory, washing, drying, precipitation obtains 2-fluoro-5-bromo nitrobenzene 142 grams (0.65mol), purity 94.12%, yield 65%.
(2) preparation of 2-fluoro-5-bromaniline
With 336 gram ethyl acetate, 112 gram lithium aluminum hydrides add in the 1L four-hole bottle, add 12ml 30% dense HCl, be warming up to 100 ℃ of activation, treat to have on bottle wall golden yellow solid to occur being activated, slowly splash into the 2-fluoro-5-bromo nitrobenzene that obtains in above-mentioned (1), dripped off in 1 hour.Continue reaction 30 minutes, track to material content less than 1% with GC, stopped reaction.Filter,, separatory, washing, drying, precipitation, weighing obtains 2-fluoro-5-bromaniline 103 grams (0.54mol), purity 94%, feed stock conversion is 100%, productive rate is 83%.
(3) preparation of 2-fluoro-5-oxygen in last of the ten Heavenly stems base aniline
The CuBr2 gram is added in the 250ml four-hole bottle, at N
2Protection down; add 2-fluoro-5-bromaniline 20 grams (0.11mol) that obtain in above-mentioned (2), decyl alcohol sodium (30%) 96 gram is heated to 120 ℃, tracks to material content less than 1% with GC; filter; washing, precipitation, drying; weigh and obtain 2-fluoro-5-oxygen in last of the ten Heavenly stems base aniline 29.4 grams (0.11mol); purity 92.44%, transformation efficiency are 100%, productive rate 100%.
Embodiment 5
(1) preparation of 2-fluoro-5-bromo nitrobenzene
O-fluoronitrobenzene 141 grams (1mol) and the vitriol oil 200 grams are added in the 500ml four-hole bottle, are cooled to 0 ℃, slowly add HBr (hydrogen bromide) 132 grams in batches, maintain the temperature at 0 ℃.After adding, its temperature is slowly gone up to 50 ℃, track to material content less than 1% with GC simultaneously, pour in the frozen water, add the extraction of 200ml ethylene dichloride, separatory, washing, drying, precipitation obtains 2-fluoro-5-bromo nitrobenzene 149 grams (0.68mol), purity 93.16%, yield 68%.
(2) preparation of 2-fluoro-5-bromaniline
With 336 gram toluene, 112 gram Raney's nickels add in the 1L four-hole bottle, add 12ml 30% dense HCl, be warming up to 120 ℃ of activation, treat to have on bottle wall golden yellow solid to occur being activated, slowly splash into the 2-fluoro-5-bromo nitrobenzene that obtains in above-mentioned (1), dripped off in 1 hour.Continue reaction 30 minutes, track to material content less than 1% with GC, stopped reaction.Filter, separatory, washing, drying, precipitation, weighing obtains 2-fluoro-5-bromaniline 101 grams (0.53mol), purity 94%, feed stock conversion is 100%, productive rate is 78.2%.
(3) preparation of 2-fluoro-5-octyloxy aniline
The CuCN2 gram is added in the 250ml four-hole bottle, at N
2Protection down; add 2-fluoro-5-bromaniline 20 grams (0.11mol) that obtain in above-mentioned (2), sad lithium alkoxide (30%) 96 gram is heated to 80 ℃, tracks to material content less than 1% with GC; filter; washing, precipitation, drying; weigh and obtain 2-fluoro-5-octyloxy aniline 26.33 grams (0.11mol); purity 91.22%, transformation efficiency are 100%, productive rate 100%.
Above-mentioned synthetic method is the synthetic route of part of compounds of the present invention, and according to above-mentioned example, those skilled in the art can synthesize other compounds of the present invention by adjusting diverse ways.The synthetic compound can further be further purified by modes such as column chromatography, high performance liquid chromatography or crystallizations.
Describe the present invention in conjunction with the embodiments above.Should be appreciated that above-mentioned explanation only is exemplary, under the situation that does not depart from the claims spirit and scope, those of ordinary skill in the art can carry out various improvement and variation to the present invention, and these improvement and variation also should comprise within the scope of the invention.
Claims (17)
1. method for preparing 2-fluoro-5-alkoxyl aniline with following structural,
R is C in the formula
1-C
10The straight or branched alkyl said method comprising the steps of:
(1) be not less than in temperature under-10 ℃ the condition, make 2-fluoronitrobenzene and bromizating agent and catalyst reaction generate 2-fluoro-5-bromo nitrobenzene, described catalyzer is the vitriol oil;
(2) with the 2-fluoro-5-bromo nitrobenzene reaction that obtains in reductive agent and the step (1), 2-fluoro-5-bromo nitrobenzene is reduced into 2-fluoro-5-bromaniline;
(3) be not less than under 60 ℃ the temperature, in the presence of catalyzer, the basic metal that 2-fluoro-5-bromaniline and general formula AOR represent or the alkyl alkoxide of alkaline-earth metal carry out the etherificate substitution reaction, obtain 2-fluoro-5-alkoxyl aniline, among its formula of AOR, A is basic metal or alkaline-earth metal, and R is C
1-C
10The straight or branched alkyl, described catalyzer is selected from CuI, CuCl, CuBr or CuCN.
2. the method for claim 1 is characterized in that described R is C
1-C
7The straight or branched alkyl.
3. method as claimed in claim 2 is characterized in that described R is C
1-C
5The straight or branched alkyl.
4. the method for claim 1 is characterized in that catalyzer used in the step (3) is CuI.
5. the method for claim 1 is characterized in that used bromizating agent is selected from bromine, C5H6Br2N2O2, NBS or HBr in the step (1), and the mol ratio of described bromizating agent consumption and 2-fluoronitrobenzene consumption is 0.5: 1-2: 1.
6. the method for claim 1, the alkyl alkoxide that it is characterized in that described basic metal or alkaline-earth metal is sodium alkyl alcohol or alkyl potassium alcoholate, the mol ratio of the alkyl alkoxide consumption of described basic metal or alkaline-earth metal and 2-fluoronitrobenzene consumption is 2: 1-10: 1.
7. method as claimed in claim 6 is characterized in that the alkyl alkoxide consumption of described basic metal or alkaline-earth metal and the mol ratio of 2-fluoronitrobenzene consumption are 3: 1-5: 1.
8. the method for claim 1 is characterized in that the temperature of reaction of step (1) is-10 ℃-50 ℃.
9. method as claimed in claim 8, the temperature of reaction that it is characterized in that step (1) are 0 ℃-20 ℃.
10. the method for claim 1, the reduction mode described in the step (2) that it is characterized in that is that metal adds acid or hydrogenating reduction method.
11. the method for claim 1 is characterized in that solvent is selected from alcohols, ethers, nitrile, aromatics, ester class or aprotic polar solvent described in the described step (2).
12. method as claimed in claim 11 is characterized in that described solvent is selected from water, aqueous ethanolic solution, ethanol, sherwood oil, acetonitrile, toluene, ethyl acetate or DMF.
13. method as claimed in claim 12 is characterized in that described solvent is an aqueous ethanolic solution.
14. the method for claim 1 is characterized in that the temperature of reaction in the described step (2) is-10 ℃-150 ℃.
15. method as claimed in claim 14 is characterized in that the temperature of reaction in the described step (2) is 30 ℃-90 ℃.
16. the method for claim 1, the temperature of reaction that it is characterized in that described step (3) are 60 ℃-120 ℃.
17. method as claimed in claim 16, the temperature of reaction that it is characterized in that described step (3) are 80 ℃-100 ℃.
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| CN102276482A (en) * | 2011-04-11 | 2011-12-14 | 常州大学 | Preparation method of 2-methoxyl-5-bromaniline |
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| CN104530107B (en) * | 2014-12-31 | 2016-08-24 | 大连联化化学有限公司 | A kind of synthetic method of 3-amino-4-fluorobenzoic boric acid |
| CN106883130B (en) * | 2017-03-23 | 2018-12-11 | 泰州百力化学股份有限公司 | A method of preparing halogenated biphenyl amine |
| CN111333516B (en) * | 2020-04-14 | 2022-09-06 | 国药集团化学试剂有限公司 | Preparation method of 2-chloro-5-bromonitrobenzene |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4006185A (en) * | 1973-07-23 | 1977-02-01 | Olin Corporation | 5-Substituted-2-fluoroanilines |
| EP0150064A2 (en) * | 1984-01-21 | 1985-07-31 | Sumitomo Chemical Company, Limited | 3-Amino-4-fluorophenylethers and their production |
-
2008
- 2008-12-31 CN CN2008102052221A patent/CN101445460B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4006185A (en) * | 1973-07-23 | 1977-02-01 | Olin Corporation | 5-Substituted-2-fluoroanilines |
| EP0150064A2 (en) * | 1984-01-21 | 1985-07-31 | Sumitomo Chemical Company, Limited | 3-Amino-4-fluorophenylethers and their production |
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| CN101445460A (en) | 2009-06-03 |
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