CN106478377A - 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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- 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
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Abstract
The invention provides a kind of synthetic method of 2,3 difluoro 5 bromophenol, with 3,4,5 trifluorobromobenzenes for raw material, comprise the steps：(1) in the presence of base, 3,4,5 trifluorobromobenzenes and alcohol is made to carry out alkoxyl substitution reaction, after reaction terminates, reactant mixture is post-treated to obtain 3,4 difluoro 5 alkoxyl bromobenzene；(2) in the presence of a lewis acid, 3,4 difluoro 5 alkoxyl bromobenzene carries out dealkylation, and after reaction terminates, reactant mixture is post-treated to obtain 2,3 difluoro 5 bromophenol.The method can with brief reactions steps, shirtsleeve operation technique, higher yield, relatively low cost synthesis of high purity 2,3 difluoro 5 bromophenol.
Description
Technical field
The present invention relates to organic synthesis field and in particular to one kind with 3,4,5- trifluorobromobenzenes be Material synthesis 2,3- bis-
The method of fluoro- 5- bromophenol.
Background technology
2,3- Difluoro-5-Bromophenols are to synthesize the important intermediate having physiology or pharmaceutically active compounds in a large number,
US20150210682, Bioorganic＆Medicinal Chemistry 23 (2015) 4375-4389, WO2015058084,
WO2014151247, WO2013065835, WO2013056003, WO2012100423, Journal of Medicinal
Chemistry, 54 (2011) 8582-8591, report this compound in synthesis in the patent such as WO2011163610 or document
There is the application in physiology or pharmaceutically active compounds.
Additionally, this compound can be used for synthesizing agricultural chemicals and liquid-crystal compoundss, purposes is increasingly extensive.This chemical combination
The molecular formula of thing is：C6H3BrF2O, structural formula is as follows.
The method of conventional introducing hydroxyl has：
(1) halogenide hydrolysis；
(2) aromatic sulfonic acid salt alkali fusion；
(3) aryl primary amine and diazonium salt hydrolysiss；
(4) nucleophilic substitutions such as hydroxyl are introduced directly into on aromatic ring to prepare alcohol and phenol
The Chinese invention patent document of Application No. 200510130822 discloses a kind of system of 2,3- Difluoro-5-Bromophenol
Preparation Method, the method, is finally produced through nitrification, reduction, bromination, deaminizating and demethylation for raw material with 2,3- difluoroanisole
Thing 2,3- Difluoro-5-Bromophenol.But, the deficiency that the method exists is：I () total recovery is relatively low, each step total recovery is only
34.9%；(ii) raw material 2,3- difluoroanisole is expensive；(iii) there may be isomerism in the sinteticses of this route
Body, is unfavorable for the highly purified requirement of TFT liquid crystal monocrystalline.
The Chinese invention patent document of Application No. 200710040272 also discloses that a kind of 2,3- Difluoro-5-Bromophenol
Synthetic method, the method with 2,3,4- trifluoronitrobenzenes be raw material, through alkoxyl replacement, reduction, bromo, deaminizating and de- alkyl
Obtain product.The method there is also the deficiencies such as many, the process complexity of reactions steps, and total recovery is only 55-65%, is difficult industrial metaplasia
Produce.
Content of the invention
It is an object of the invention to provide a kind of synthetic method of 2,3- Difluoro-5-Bromophenol, the method can be with brief
Reactions steps, shirtsleeve operation technique, higher yield, the 2,3- Difluoro-5-Bromophenol of relatively low cost synthesis of high purity.
The technical solution used in the present invention is as follows：A kind of synthetic method of 2,3- Difluoro-5-Bromophenol, with 3,4,5- trifluoros
Bromobenzene is raw material, comprises the steps：
(1) in the presence of base, 3,4,5- trifluorobromobenzenes and alcohol is made to carry out alkoxyl substitution reaction, after reaction terminates, instead
Answer the post-treated fluoro- 5- alkoxyl bromobenzene of 3,4- bis- obtaining as shown in formula (I) of mixture；
In formula, R is C1～C8 alkyl；
(2) in the presence of a lewis acid, the fluoro- 5- alkoxyl bromobenzene of 3,4- bis- carries out dealkylation, after reaction terminates,
Reactant 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), described alcohol is C1～C8 alcohol.Preferably, described alcohol is C1～C3 alcohol.
Described alcohol is 1～10 with the mass ratio of 3,4,5- trifluorobromobenzene:1.Preferably, described alcohol and 3,4,5- tri-
The mass ratio of bromofluorobenzene is 2～5:1.When the consumption of alcohol is very few, reaction is not thorough, can reduce production efficiency when consumption is excessive.
In step (1), described alkali is sodium hydroxide, potassium hydroxide, Lithium hydrate, calcium hydroxide or magnesium hydroxide, makees
It is potassium hydroxide for preferred, described alkali.Described alkali is 1～10 with the mol ratio of 3,4,5- trifluorobromobenzene:1, preferably, institute
The mol ratio stating alkali with 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 affect response speed, improve reaction temperature
Response speed can be increased, but also can affect the selectivity of alkyl substitution simultaneously, cause secondary replacement, and increase high boiling product
Growing amount, 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 more than 99%, and in course of reaction, basic isomer-free generates, only a small amount of height
Boiling product.
The response time of step (1) is 3～10h, preferably, the response time of step (1) is 4～6h.
The post-processing approach of step (1) is：After reaction terminates, reactant liquor directly freezed to -15～5 DEG C, separate out crystal, mistake
Filter is isolated crystal and is the fluoro- 5- alkoxyl bromobenzene of 3,4- bis-.
In step (2), described lewis acid is aluminum chloride, zinc chloride or boron trifluoride diethyl etherate, preferably, combining anti-
Answer activity and cost, described lewis acid is aluminum chloride.Described lewis acid and the fluoro- 5- alkoxyl bromobenzene of 3,4- bis- mole
Than for 1～3:1, preferably, the mol ratio of described lewis acid and the fluoro- 5- alkoxyl bromobenzene of 3,4- bis- is 1.2～1.8:1.
In step (2), described reaction is carried out in organic solvent, and the organic solvent of selection is methanol, ethanol, propanol, different
Propanol, toluene, dimethylbenzene, ethyl acetate, dichloroethanes, chloroform, N-Methyl pyrrolidone, oxolane, methyl tertiary butyl ether(MTBE)
Or N,N-dimethylformamide.The fluoro- 5- alkoxyl bromobenzene of 3,4- bis- is 0.1～0.2g/mL with the amount ratio of organic solvent.
The reaction temperature of step (2) is 60～140 DEG C, preferably, the reaction temperature of step (2) is 80～120 DEG C.
The response time of step (2) is 3～10h, preferably, the response time of step (2) is 4～7h.
The post-processing approach of step (2) is：After reaction terminates, washed reaction liquid, layering, take out upper organic layer, normal pressure
Or after boiling off organic solvent under decompression, then vacuum distillation obtains product 2,3- Difluoro-5-Bromophenol.
Compared with prior art, the invention has the advantages that：
(1) raw material that synthetic method of the present invention is used is commercialized raw materials；
(2) synthetic route of the present invention is short, only comprises two-step reaction, and technological operation is simple, need not special equipment, have good
Good industrial applications prospect；
(3) reaction condition of the present invention is gentle, and side reaction is few, product yield high, optimized after, two step total recoverys are 80%
More than.
Brief description
Fig. 1 is the process chart of the present invention.
Specific embodiment
Embodiment 1
(1) add 84.4g 3,4,5- trifluorobromobenzene toward the tetra- mouthfuls of reaction bulbs of 1000mL being furnished with magneton and reflux condensing tube
(0.4mol), 500mL methanol and 67.2g KOH (1.2mol), charging is warming up to 60 DEG C after finishing, stirring reaction 6h, gas phase color
Reaction process followed the tracks of by spectrometer, till raw material fundamental reaction is complete.After reaction terminates, reactant liquor is freezed 5h at -10 DEG C, has
A large amount of crystal separate out, and sucking filtration separates and obtains crystal 80.0g, and this crystal GC normalization method records the fluoro- 5- bromoanisole of 2,3- bis- and contains
Measure as 99.2%.Methanol Recovery can reuse.
(2) in being furnished with tetra- mouthfuls of reaction bulbs of 1000mL of magneton and reflux condensing tube, add 80.0g 2 obtained above,
The fluoro- 5- bromoanisole (0.36mol) of 3- bis-, the toluene of 600mL and 71.8g AlCl3(0.54mol).It is warming up under nitrogen protection
80 DEG C, stirring reaction 5h, gas chromatogram follows the tracks of reaction process, until till the fluoro- 5- bromoanisole fundamental reaction of 2,3- bis- is complete.Instead
After should terminating, washed reaction liquid, separate upper strata, revolving removes toluene, vacuum distillation obtains 2,3- Difluoro-5-Bromophenol 67.7g,
GC assay products content is 99.3%.Reclaim toluene drying and process and can reuse.
After testing, the nuclear magnetic spectrogram of gained target product compares consistent, two-step reaction total recovery with mass spectrum and standard substance
For：81.0%.
Embodiment 2
(1) add 84.4g 3,4,5- trifluorobromobenzene toward the tetra- mouthfuls of reaction bulbs of 1000mL being furnished with magneton and reflux condensing tube
(0.4mol), 400mL ethanol and 44.9g KOH (0.8mol), charging is warming up to 80 DEG C after finishing, stirring reaction 4h, gas phase color
Reaction process followed the tracks of by spectrometer, till raw material fundamental reaction is complete.After reaction terminates, reactant liquor is freezed 6h at -5 DEG C, has
A large amount of crystal separate out, and sucking filtration separates and obtains crystal 86.3g, and this crystal GC normalization method records the fluoro- 5- Bromoethyl phenyl ether of 2,3- bis- and contains
Measure as 99.3%.Ethanol reclaims and can reuse.
(2) in being furnished with tetra- mouthfuls of reaction bulbs of 1000mL of magneton and reflux condensing tube, add 86.3g 2 obtained above,
The fluoro- 5- Bromoethyl phenyl ether (0.364mol) of 3- bis-, the toluene of 500mL and 97.0g AlCl3(0.728mol).Nitrogen protection is lower to heat up
To 70 DEG C, stirring reaction 6h, gas chromatogram follows the tracks of reaction process, until till the fluoro- 5- Bromoethyl phenyl ether fundamental reaction of 2,3- bis- is complete.
After reaction terminates, washed reaction liquid, separate upper strata, revolving removes toluene, vacuum distillation obtains 2,3- Difluoro-5-Bromophenol
68.1g, GC assay products content is 99.2%.Reclaim toluene drying and process and can reuse.
Two-step reaction total recovery is：81.3%.
Embodiment 3
(1) add 84.4g 3,4,5- trifluorobromobenzene toward the tetra- mouthfuls of reaction bulbs of 1000mL being furnished with magneton and reflux condensing tube
(0.4mol), 300mL propanol and 89.6g KOH (1.6mol), charging is warming up to 90 DEG C after finishing, stirring reaction 4h, gas phase color
Reaction process followed the tracks of by spectrometer, till raw material fundamental reaction is complete.After reaction terminates, reactant liquor is freezed 8h at 0 DEG C, have big
Amount crystal separates out, and sucking filtration separates and obtains crystal 90.9g, and this crystal GC normalization method records the fluoro- 5- bromobenzene propyl ether content of 2,3- bis-
For 99.0%.Propanol reclaims and can reuse.
(2) in being furnished with tetra- mouthfuls of reaction bulbs of 1000mL of magneton and reflux condensing tube, add 90.9g 2 obtained above,
Fluoro- 5- bromobenzene propyl ether (0.362mol) of 3- bis-, the dimethylbenzene of 700mL and 62.7g AlCl3(0.47mol).Rise under nitrogen protection
Temperature to 100, stirring reaction 4h, gas chromatogram follows the tracks of reaction process, until the fluoro- 5- bromobenzene propyl ether fundamental reaction of 2,3- bis- is complete being
Only.After reaction terminates, washed reaction liquid, separate upper strata, revolving removes toluene, vacuum distillation obtains 2,3- Difluoro-5-Bromophenol
67.5g, GC assay products content is 99%.Reclaim dimethylbenzene drying and process and can reuse.
Two-step reaction total recovery is：80.7%.
Embodiment 4
Course of reaction is same as Example 1, except that in step (2), solvent is 500mL oxolane,
Reaction temperature is 65 DEG C, stirring reaction 7h.
Finally give 2,3- Difluoro-5-Bromophenol 66.3g, GC assay products content is 99.1%.Reclaim oxolane warp
Dried can reuse.
Two-step reaction total recovery is：79.3%.
Embodiment 5
Course of reaction is same as Example 1, except that in step (1), alkali is 48.0g NaOH
(1.2mol), sucking filtration separates and obtains crystal 78.1g, and this crystal GC normalization method records the fluoro- 5- bromoanisole content of 2,3- bis- and is
99.0%.
After step (2) reaction, finally give 2,3- Difluoro-5-Bromophenol 64.4g, GC assay products content is
99.2%.
Two-step reaction total recovery is：77%.
Embodiment 6
Course of reaction is same as Example 1, except that in step (2), lewis acid is that 62.3g is borontrifluoride
Borate ether (29.3g containing boron trifluoride, 0.432mol).
Finally give 2,3- Difluoro-5-Bromophenol 67.6g, GC assay products content is 99.3%.
Two-step reaction total recovery is：80.5%.
Embodiment 7：
(1) add 201.6kg KOH in 3000L reactor, pump into 253.2kg 3,4,5- trifluorobromobenzene and 1500L first
Alcohol, closed reactor, it is warming up to 60 DEG C under stirring, sample analysis after reaction 6h, raw material fundamental reaction is complete.Material nitrogen
Air pressure enters crystallizing pan, and stirring is cooled to -5 DEG C, and insulation 5h filters, and 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 reactor3, then pump
Enter the toluene of 1800L, closed reactor, be heated to reflux sample analysis after 5h, raw material fundamental reaction is complete.Material nitrogen
The washing kettle of press-in 5000L, pumps into 1000L water agitator treating, discards water layer, repeats and several is laminated into steaming having after washed once
Evaporate kettle, after boiling off toluene, after vacuum distillation, obtain 2, the 3- Difluoro-5-Bromophenol of 206.1kg, GC assay products content is
99.4%.Reclaim toluene drying and process and can reuse.
Two-step reaction total recovery is：82.2%.
Claims (10)
1. one kind 2, the synthetic method of 3- Difluoro-5-Bromophenol it is characterised 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 is made to carry out alkoxyl substitution reaction, after reaction terminates, reaction is mixed
The post-treated fluoro- 5- alkoxyl bromobenzene of 3,4- bis- obtaining as shown in formula (I) of compound；
In formula, R is C1～C8 alkyl；
(2) in the presence of a lewis acid, the fluoro- 5- alkoxyl bromobenzene of 3,4- bis- carries out dealkylation, after reaction terminates, reaction
Mixture is post-treated to obtain 2,3- Difluoro-5-Bromophenol.
2. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1 is it is characterised in that in step (1), institute
The alcohol stated is C1～C8 alcohol.
3. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1 is it is characterised in that described alcohol and 3,
The mass ratio of 4,5- trifluorobromobenzene is 1～10:1.
4. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1 is it is characterised in that in step (1), institute
The alkali stated is sodium hydroxide, potassium hydroxide, Lithium hydrate, calcium hydroxide or magnesium hydroxide；Described alkali and 3,4,5- trifluorobromobenzene
Mol ratio be 1～10:1.
5. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1 is it is characterised in that the reaction of step (1)
Temperature is 40～140 DEG C.
6. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1 is it is characterised in that the rear place of step (1)
Reason method is：After reaction terminates, reactant liquor directly freezed to -15～5 DEG C, separate out crystal, filter to isolate crystal and be 3,4-
Two fluoro- 5- alkoxyl bromobenzenes.
7. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1 is it is characterised in that in step (2), institute
The lewis acid stated is aluminum chloride, zinc chloride or boron trifluoride diethyl etherate；Described lewis acid and the fluoro- 5- alkoxyl bromobenzene of 3,4- bis-
Mol ratio be 1～3:1.
8. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1 is it is characterised in that in step (2), institute
State reaction to carry out in organic solvent, the organic solvent of selection is methanol, ethanol, propanol, isopropanol, toluene, dimethylbenzene, acetic acid
Ethyl ester, dichloroethanes, chloroform, N-Methyl pyrrolidone, oxolane, methyl tertiary butyl ether(MTBE) or N,N-dimethylformamide.
9. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1 is it is characterised in that the reaction of step (2)
Temperature is 60～140 DEG C.
10. the synthetic method of 2,3- Difluoro-5-Bromophenol according to claim 1 is it is characterised in that after step (2)
Processing method is：After reaction terminates, washed reaction liquid, layering, take out upper organic layer, under normal pressure or decompression, boil off organic solvent
Afterwards, then vacuum distillation obtains product 2,3- Difluoro-5-Bromophenol.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108069831A (en) * | 2018-01-25 | 2018-05-25 | 上海恩氟佳科技有限公司 | A kind of method for synthesizing 2,3- dimethyl -4- fluorophenols |
| CN108558618A (en) * | 2018-05-28 | 2018-09-21 | 朱晓萍 | A method of preparing 2,3- difluorophenols |
| CN108586204A (en) * | 2018-05-28 | 2018-09-28 | 朱晓萍 | A kind of synthesis technology of 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108069831A (en) * | 2018-01-25 | 2018-05-25 | 上海恩氟佳科技有限公司 | A kind of method for synthesizing 2,3- dimethyl -4- fluorophenols |
| CN108558618A (en) * | 2018-05-28 | 2018-09-21 | 朱晓萍 | A method of preparing 2,3- difluorophenols |
| CN108586204A (en) * | 2018-05-28 | 2018-09-28 | 朱晓萍 | A kind of synthesis technology of 2,3- difluorophenols |
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