CN106478377B - A kind of synthetic method of 2,3- Difluoro-5-Bromophenol - Google Patents
A kind of synthetic method of 2,3- Difluoro-5-Bromophenol Download PDFInfo
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- CN106478377B CN106478377B CN201610748258.9A CN201610748258A CN106478377B CN 106478377 B CN106478377 B CN 106478377B CN 201610748258 A CN201610748258 A CN 201610748258A CN 106478377 B CN106478377 B CN 106478377B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
Abstract
The present invention provides one kind 2, the synthetic method of 3- Difluoro-5-Bromophenol, with 3,4,5- trifluorobromobenzene is raw material, include the following steps: (1) in the presence of base, makes 3,4,5- trifluorobromobenzene and alcohol carry out alkoxy substitution reaction, after reaction, reaction mixture is post-treated obtains the fluoro- 5- alkoxy bromobenzene of 3,4- bis-；(2) in the presence of a lewis acid, the fluoro- 5- alkoxy bromobenzene of 3,4- bis- carries out dealkylation, and after reaction, reaction mixture is post-treated to obtain 2,3- Difluoro-5-Bromophenol.This method can synthesize the 2,3- Difluoro-5-Bromophenol of high-purity with brief reaction step, shirtsleeve operation technique, higher yield, lower cost.
Description
Technical field
The present invention relates to organic synthesis fields, and in particular to it is a kind of with 3,4,5- trifluorobromobenzenes for Material synthesis 2,3- bis-
The method of fluoro- 5- bromophenol.
Background technique
2,3- Difluoro-5-Bromophenols are the important intermediates that synthesis largely has physiology or pharmaceutically active compounds,
US20150210682, Bioorganic&Medicinal Chemistry 23 (2015) 4375-4389, WO2015058084,
WO2014151247, WO2013065835, WO2013056003, WO2012100423, Journal of Medicinal
Chemistry, 54 (2011) 8582-8591 report the compound in the patents such as WO2011163610 or document and are synthesizing
With the application in physiology or pharmaceutically active compounds.
In addition, the compound can be used for synthesis agricultural chemicals and liquid-crystal compounds, purposes are increasingly extensive.The chemical combination
The molecular formula of object are as follows: C6H3BrF2O, structural formula are as follows.
The common method for introducing hydroxyl has:
(1) halide hydrolyzes；
(2) aromatic sulfonic acid salt alkali fusion；
(3) aryl primary amine and diazonium salt hydrolysis；
(4) nucleophilic substitutions such as hydroxyl are introduced directly on aromatic ring to prepare alcohol and phenol
Application No. is 200510130822 Chinese invention patent documents to disclose a kind of fluoro- 5- bromophenol of 2,3- bis-
Preparation method, this method, for raw material, are obtained finally with 2,3- difluoroanisole through nitrification, reduction, bromination, deamination and demethylation
Product 2,3- Difluoro-5-Bromophenol.But deficiency existing for this method is: (i) total recovery is lower, and each total recovery that walks is only
34.9%；(ii) raw material 2,3- difluoroanisole is expensive；(iii) there may be isomerisms in the sintetics of the route
Body is unfavorable for the requirement of TFT liquid crystal monocrystalline high-purity.
Application No. is 200710040272 Chinese invention patent documents to also disclose a kind of 2,3- Difluoro-5-Bromophenol
Synthetic method, this method with 2,3,4- trifluoronitrobenzenes be raw material, through alkoxy substitution, reduction, bromo, deamination and de- alkane
Base obtains product.This method there is also reaction steps it is more, process is complicated the deficiencies of, total recovery is only 55-65%, is not easy to industrialize
Production.
Summary of the invention
The purpose of the present invention is to provide the synthetic method of one kind 2,3- Difluoro-5-Bromophenol, this method can be with brief
Reaction step, shirtsleeve operation technique, higher yield, lower cost synthesis high-purity 2,3- Difluoro-5-Bromophenol.
The technical solution adopted by the invention is as follows: the synthetic method of one kind 2,3- Difluoro-5-Bromophenol, with 3,4,5- tri-
Bromofluorobenzene is raw material, is included the following steps:
(1) in the presence of base, 3,4,5- trifluorobromobenzenes and alcohol are made to carry out alkoxy substitution reaction, after reaction, instead
Answer mixture is post-treated to obtain the fluoro- 5- alkoxy bromobenzene of 3,4- bis- as shown in formula (I)；
In formula, R is C1~C8 alkyl；
(2) in the presence of a lewis acid, the fluoro- 5- alkoxy bromobenzene of 3,4- bis- carries out dealkylation, after reaction,
Reaction mixture is post-treated to obtain 2,3- Difluoro-5-Bromophenol.
The net reaction of the synthetic method of 2,3- Difluoro-5-Bromophenol of the present invention is as follows:
In formula, R is C1~C8 alkyl.
In step (1), the alcohol is C1~C8 alcohol.Preferably, the alcohol is C1~C3 alcohol.
The mass ratio of the alcohol and 3,4,5- trifluorobromobenzene is 1~10:1.Preferably, the alcohol and 3,4,5-
The mass ratio of trifluorobromobenzene is 2~5:1.Reaction is not thorough when the dosage of alcohol is very few, and production efficiency can be reduced when dosage is excessive.
In step (1), the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or magnesium hydroxide, is made
To be preferred, the alkali is potassium hydroxide.The molar ratio of the alkali and 3,4,5- trifluorobromobenzenes is 1~10:1, preferably, institute
The molar ratio for stating alkali and 3,4,5- trifluorobromobenzene is 1.5~5:1.
The reaction temperature of step (1) is 40~140 DEG C, and reaction temperature is too low to will affect reaction speed, improves reaction temperature
It can increase reaction speed, but also will affect the selectivity of alkyl substitution simultaneously, cause secondary substitution, and increase high boiling product
Production quantity, reduce product yield.Preferably, the reaction temperature of step (1) is 60~100 DEG C, in preferred reaction temperature
Under, the selectivity of substitution reaction product can reach 99% or more, and basic isomer-free generates in reaction process, only a small amount of height
Boil product.
The reaction time of step (1) is 3~10h, preferably, the reaction time of step (1) is 4~6h.
The post-processing approach of step (1) are as follows: after reaction, reaction solution directly freezed is precipitated crystal to -15~5 DEG C, mistake
It is the fluoro- 5- alkoxy bromobenzene of 3,4- bis- that crystal is isolated in filter.
In step (2), the lewis acid is aluminium chloride, zinc chloride or boron trifluoride ether, preferably, combining anti-
Activity and cost are answered, the lewis acid is aluminium chloride.Mole of the lewis acid and the fluoro- 5- alkoxy bromobenzene of 3,4- bis-
Than for 1~3:1, preferably, the lewis acid and 3, the molar ratio of the fluoro- 5- alkoxy bromobenzene of 4- bis- is 1.2~1.8:1.
In step (2), the reaction carries out in organic solvent, and the organic solvent of selection is methanol, ethyl alcohol, propyl alcohol, different
Propyl alcohol, toluene, dimethylbenzene, ethyl acetate, dichloroethanes, chloroform, N- methyl pyrrolidone, tetrahydrofuran, methyl tertiary butyl ether(MTBE)
Or N,N-dimethylformamide.The amount ratio of the fluoro- 5- alkoxy bromobenzene of 3,4- bis- and organic solvent is 0.1~0.2g/mL.
The reaction temperature of step (2) is 60~140 DEG C, preferably, the reaction temperature of step (2) is 80~120 DEG C.
The reaction time of step (2) is 3~10h, preferably, the reaction time of step (2) is 4~7h.
The post-processing approach of step (2) are as follows: after reaction, upper organic layer, normal pressure are taken out in washed reaction liquid, layering
Or it after under decompression boiling off organic solvent, then is evaporated under reduced pressure to obtain product 2,3- Difluoro-5-Bromophenol.
Compared with prior art, the invention has the following advantages:
(1) raw material used in synthetic method of the present invention is commercialized raw materials；
(2) synthetic route of the invention is short, only includes two-step reaction, and technological operation is simple, is not necessarily to special equipment, has good
Good industrial applications prospect；
(3) reaction condition of the invention is mild, and side reaction is few, product yield high, and after optimized, two step total recoverys are 80%
More than.
Detailed description of the invention
Fig. 1 is process flow chart of the invention.
Specific embodiment
Embodiment 1
(1) 84.4g 3,4,5- trifluorobromobenzene is added toward tetra- mouthfuls of reaction flasks of 1000mL equipped with magneton and reflux condensing tube
(0.4mol), 500mL methanol and 67.2g KOH (1.2mol), are warming up to 60 DEG C after charging, be stirred to react 6h, gas phase color
Spectrometer tracks reaction process, until raw material fundamental reaction is complete.After reaction, reaction solution is freezed into 5h at -10 DEG C, had
A large amount of crystal are precipitated, and filter isolated crystal 80.0g, crystal GC normalization method measures the fluoro- 5- bromoanisole of 2,3- bis- and contains
Amount is 99.2%.Methanol Recovery can reuse.
(2) in tetra- mouthfuls of reaction flasks of 1000mL equipped with magneton and reflux condensing tube, 80.0g 2 obtained above is added,
The fluoro- 5- bromoanisole (0.36mol) of 3- bis-, 600mL toluene and 71.8g AlCl3(0.54mol).It heats up under nitrogen protection
To 80 DEG C, it is stirred to react 5h, gas-chromatography tracks reaction process, until until the fluoro- 5- bromoanisole fundamental reaction of 2,3- bis- is complete.
After reaction, washed reaction liquid separates upper layer, and revolving removes toluene, and vacuum distillation obtains 2,3- Difluoro-5-Bromophenol
It is 99.3% that 67.7g, GC, which analyze product assay,.Recycling toluene can be reused through being dried.
Through detecting, the nuclear magnetic spectrogram and mass spectrogram and standard items of gained target product are compared unanimously, two-step reaction total recovery
Are as follows: 81.0%.
Embodiment 2
(1) 84.4g 3,4,5- trifluorobromobenzene is added toward tetra- mouthfuls of reaction flasks of 1000mL equipped with magneton and reflux condensing tube
(0.4mol), 400mL ethyl alcohol and 44.9g KOH (0.8mol), are warming up to 80 DEG C after charging, be stirred to react 4h, gas phase color
Spectrometer tracks reaction process, until raw material fundamental reaction is complete.After reaction, reaction solution is freezed into 6h at -5 DEG C, had
A large amount of crystal are precipitated, and filter isolated crystal 86.3g, crystal GC normalization method measures the fluoro- 5- Bromoethyl phenyl ether of 2,3- bis- and contains
Amount is 99.3%.Ethyl alcohol recycling can reuse.
(2) in tetra- mouthfuls of reaction flasks of 1000mL equipped with magneton and reflux condensing tube, 86.3g 2 obtained above is added,
The fluoro- 5- Bromoethyl phenyl ether (0.364mol) of 3- bis-, 500mL toluene and 97.0g AlCl3(0.728mol).It is risen under nitrogen protection
Temperature is stirred to react 6h to 70 DEG C, and gas-chromatography tracks reaction process, is up to the fluoro- 5- Bromoethyl phenyl ether fundamental reaction of 2,3- bis- is complete
Only.After reaction, washed reaction liquid separates upper layer, and revolving removes toluene, and vacuum distillation obtains 2,3- Difluoro-5-Bromophenol
It is 99.2% that 68.1g, GC, which analyze product assay,.Recycling toluene can be reused through being dried.
Two-step reaction total recovery are as follows: 81.3%.
Embodiment 3
(1) 84.4g 3,4,5- trifluorobromobenzene is added toward tetra- mouthfuls of reaction flasks of 1000mL equipped with magneton and reflux condensing tube
(0.4mol), 300mL propyl alcohol and 89.6g KOH (1.6mol), are warming up to 90 DEG C after charging, be stirred to react 4h, gas phase color
Spectrometer tracks reaction process, until raw material fundamental reaction is complete.After reaction, reaction solution is freezed into 8h at 0 DEG C, had big
It measures crystal to be precipitated, filters isolated crystal 90.9g, crystal GC normalization method measures the fluoro- 5- bromobenzene propyl ether content of 2,3- bis-
It is 99.0%.Propyl alcohol recycling can reuse.
(2) in tetra- mouthfuls of reaction flasks of 1000mL equipped with magneton and reflux condensing tube, 90.9g 2 obtained above is added,
The fluoro- 5- bromobenzene propyl ether (0.362mol) of 3- bis-, 700mL dimethylbenzene and 62.7g AlCl3(0.47mol).It is risen under nitrogen protection
Temperature is stirred to react 4h, gas-chromatography tracks reaction process, is up to the fluoro- 5- bromobenzene propyl ether fundamental reaction of 2,3- bis- is complete to 100
Only.After reaction, washed reaction liquid separates upper layer, and revolving removes toluene, and vacuum distillation obtains 2,3- Difluoro-5-Bromophenol
It is 99% that 67.5g, GC, which analyze product assay,.Recycling dimethylbenzene can be reused through being dried.
Two-step reaction total recovery are as follows: 80.7%.
Embodiment 4
Reaction process is same as Example 1, except that solvent is 500mL tetrahydrofuran in step (2),
Reaction temperature is 65 DEG C, is stirred to react 7h.
2,3- Difluoro-5-Bromophenol 66.3g is finally obtained, it is 99.1% that GC, which analyzes product assay,.Recycle tetrahydrofuran warp
Drying process can reuse.
Two-step reaction total recovery are as follows: 79.3%.
Embodiment 5
Reaction process is same as Example 1, except that alkali is 48.0g NaOH in step (1)
(1.2mol), filters isolated crystal 78.1g, and crystal GC normalization method measures the fluoro- 5- bromoanisole content of 2,3- bis- and is
99.0%.
After step (2) reaction, 2,3- Difluoro-5-Bromophenol 64.4g is finally obtained, GC analysis product assay is
99.2%.
Two-step reaction total recovery are as follows: 77%.
Embodiment 6
Reaction process is same as Example 1, except that lewis acid is 62.3g borontrifluoride in step (2)
Borate ether (29.3g containing boron trifluoride, 0.432mol).
2,3- Difluoro-5-Bromophenol 67.6g is finally obtained, it is 99.3% that GC, which analyzes product assay,.
Two-step reaction total recovery are as follows: 80.5%.
Embodiment 7:
(1) 201.6kg KOH is added in 3000L reaction kettle, is pumped into 3,4,5- trifluorobromobenzene of 253.2kg and 1500L first
Alcohol, closed reactor are warming up to 60 DEG C under stirring, react sampling analysis after 6h, fundamental reaction is complete for raw material.Material nitrogen
Air pressure enters crystallizing pan, and stirring is cooled to -5 DEG C, and heat preservation 5h filtering obtains the fluoro- 5- bromoanisole of 2,3- bis-, yield 92.0% contains
Amount 99.2%.Methanol Recovery in filtrate can reuse.
(2) the fluoro- 5- bromoanisole of 2,3- bis- obtained above and 215kg AlCl are added in 3000L reaction kettle3, then pump
Enter the toluene of 1800L, closed reactor is heated to reflux sampling analysis after 5h, and fundamental reaction is complete for raw material.Material nitrogen
It is pressed into the washing kettle of 5000L, 1000L water agitator treating is pumped into, discards water layer, repeats and several is laminated into steaming having after washed once
Kettle is evaporated, 2, the 3- Difluoro-5-Bromophenol of 206.1kg is obtained after boiling off toluene, after vacuum distillation, GC analysis product assay is
99.4%.Recycling toluene can be reused through being dried.
Two-step reaction total recovery are as follows: 82.2%.
Claims (7)
1. one kind 2, the synthetic method of 3- Difluoro-5-Bromophenol, which is characterized in that with 3,4,5- trifluorobromobenzenes for raw material, including
Following steps:
(1) in the presence of base, 3,4,5- trifluorobromobenzenes and alcohol are made to carry out alkoxy substitution reaction, after reaction, reaction is mixed
Close that object is post-treated obtains the fluoro- 5- alkoxy bromobenzene of 3,4- bis- as shown in formula (I)；
In formula, R is C1~C3 alkyl；
(2) in the presence of a lewis acid, the fluoro- 5- alkoxy bromobenzene of 3,4- bis- carries out dealkylation, after reaction, reaction
Mixture is post-treated to obtain 2,3- Difluoro-5-Bromophenol；
In step (1), the alkali is potassium hydroxide, and the alkali and 3, the molar ratio of 4,5- trifluorobromobenzenes is 1.5~5:1；Institute
The alcohol stated is C1~C3 alcohol；
The post-processing approach of step (1) are as follows: after reaction, reaction solution directly freezed is precipitated crystal to -15~5 DEG C, filtering point
Separating out crystal is the fluoro- 5- alkoxy bromobenzene of 3,4- bis-.
2. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1, which is characterized in that the alcohol and 3,
The mass ratio of 4,5- trifluorobromobenzene is 1~10:1.
3. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1, which is characterized in that the reaction of step (1)
Temperature is 40~140 DEG C.
4. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1, which is characterized in that in step (2), institute
The lewis acid stated is aluminium chloride, zinc chloride or boron trifluoride ether；The lewis acid and the fluoro- 5- alkoxy bromobenzene of 3,4- bis-
Molar ratio be 1~3:1.
5. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1, which is characterized in that in step (2), institute
It states reaction to carry out in organic solvent, the organic solvent of selection is methanol, ethyl alcohol, propyl alcohol, isopropanol, toluene, dimethylbenzene, acetic acid
Ethyl ester, dichloroethanes, chloroform, N-Methyl pyrrolidone, tetrahydrofuran, methyl tertiary butyl ether(MTBE) or N,N-dimethylformamide.
6. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1, which is characterized in that the reaction of step (2)
Temperature is 60~140 DEG C.
7. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1, which is characterized in that the rear place of step (2)
Reason method are as follows: after reaction, washed reaction liquid, layering takes out upper organic layer, boils off organic solvent under normal pressure or decompression
Afterwards, it then is evaporated under reduced pressure to obtain product 2,3- Difluoro-5-Bromophenol.
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| CN108558618A (en) * | 2018-05-28 | 2018-09-21 | 朱晓萍 | A method of preparing 2,3- difluorophenols |
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| CN1789224A (en) * | 2005-12-20 | 2006-06-21 | 阜新金鸿泰化工有限公司 | Preparation method of 2.3-difluoro-5-bromophenol |
| CN101037380A (en) * | 2007-04-29 | 2007-09-19 | 上海康鹏化学有限公司 | Preparation method of 2,3-Difluoro-5-Bromophenol |
| CN101407451A (en) * | 2008-03-27 | 2009-04-15 | 河北迈尔斯通电子材料有限公司 | Preparation method of 3,5-difluoroanisole |
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| CN1789224A (en) * | 2005-12-20 | 2006-06-21 | 阜新金鸿泰化工有限公司 | Preparation method of 2.3-difluoro-5-bromophenol |
| CN101037380A (en) * | 2007-04-29 | 2007-09-19 | 上海康鹏化学有限公司 | Preparation method of 2,3-Difluoro-5-Bromophenol |
| CN101407451A (en) * | 2008-03-27 | 2009-04-15 | 河北迈尔斯通电子材料有限公司 | Preparation method of 3,5-difluoroanisole |
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