CN106673964A - Method for preparing 2,3,4,5,6-pentafluorophenol - Google Patents
Method for preparing 2,3,4,5,6-pentafluorophenol Download PDFInfo
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- CN106673964A CN106673964A CN201510746066.XA CN201510746066A CN106673964A CN 106673964 A CN106673964 A CN 106673964A CN 201510746066 A CN201510746066 A CN 201510746066A CN 106673964 A CN106673964 A CN 106673964A
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- IXVPURPITBBZEG-UHFFFAOYSA-N Cc(c(N)c(c(OC)c1N)N)c1N Chemical compound Cc(c(N)c(c(OC)c1N)N)c1N IXVPURPITBBZEG-UHFFFAOYSA-N 0.000 description 1
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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
Abstract
The invention discloses a method for preparing 2,3,4,5,6-pentafluorophenol. The method comprises the following step of in water, performing an oxidation reaction on 2,3,4,5,6-pentafluoro phenylboronic acid as shown in the formula (VI) and hydrogen peroxide, thereby obtaining 2,3,4,5,6-pentafluorophenol as shown in the formula (VII). According to the method, an oxidation reaction is implemented in the water, so that the method is low in cost, and environmental-friendly; and besides, the method is high in reaction yield and purity and relatively applicable to industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of 2,3,4,5,6- Pentafluorophenols.
Background technology
Pentafluorophenol is many fluorine class liquid-crystal compounds, is a kind of important fine chemicals, and it is both medicine
Intermediate, pesticide intermediate, are also the intermediate for preparing high-performance liquid crystal material.Many fluorine class LCD compounds
After thing is used in mixed way with low viscosity and high dielectric anisotropy nematic liquid crystalline material, molecule can be increased
Dipole moment, reduces the response time, improves the display performance of liquid crystal material, improves definition, high to production
Performance liquid crystal material has great importance.
At present, industrially mainly Pentafluorophenol is prepared using penta phenyl fluoride boron acid oxidation, the method is usually
With five bromofluorobenzenes or phenyl-pentafluoride as initiation material, pentafluorophenyl boric acid is prepared by RMgBr or lithium reagent,
Again obtained pentafluorophenyl boric acid is generated into organic solvent Pentafluorophenol, last essence with peroxide reactions
Evaporate and obtain Pentafluorophenol, its reaction stream formula is as follows：
Patent CN1847210A discloses a kind of preparation method of Pentafluorophenol, and specifically discloses：
(1) in 500mL four-hole bottles add magnesium chips 12.6g (0.52mol), 1 granule crystal iodine and
THF150mL, N250 DEG C are heated under protection, are added dropwise by the fluorine bromines of 123.5g (0.50mol) five
The solution that benzene and 120mLTHF are made into, temperature 50 C～55 DEG C finish continuation and are incubated 2 hours, cooling
To room temperature.Product is RMgBr.
(2) the isobutyl ester 117.5g (0.625mol) of boric acid three, tetrahydrofuran are put into there-necked flask
250mL opens stirring so as to become mixed solution, when this solution is cooled to -20 DEG C, previous step is added dropwise
Reactant RMgBr, temperature -15～-20 DEG C.After completion of dropping, 10 minutes are incubated, then are added dropwise 10%
Hydrochloric acid solution 300mL.Distillation recovery tetrahydrofuran, residue crystallisation by cooling is filtered, and obtains penta phenyl fluoride boron
Sour wet product.
(3) above-mentioned penta phenyl fluoride boron acid crude is put into there-necked flask, while plus dichloroethanes 250mL,
Opening stirring dissolves it, and control temperature is added dropwise 30% hydrogen peroxide 85g (0.75mol) at 15 DEG C～20 DEG C,
After completion of dropping, then insulation reaction is stirred 15 hours in this temperature, after insulation terminates, with the Asia of saturation
Sodium sulphate washing eliminates excessive hydrogen peroxide, and oil reservoir is separated after standing.The air-distillation of oil reservoir elder generation steams solvent,
Product frac is collected in rectification under vacuum again, can obtain white Pentafluorophenol crystal, yield 55%.
A kind of preparation method of Pentafluorophenol is disclosed in patent CN103420801A, and is specifically disclosed：
(1) 1000mL four-hole bottles are dried, nitrogen displacement, opens stirring and keep good nitrogen to protect
Shield, 365mLTHF, 200g (0.81mol) five bromofluorobenzene is added into four-hole bottle, under stirring,
Isopropylmagnesium chloride/THF solution 415mL (0.83mol) is added dropwise at 40 DEG C～50 DEG C, then at 40 DEG C
～50 DEG C of scopes are incubated 2 hours.
(2) 500mLTHF and 97g (0.94mol) boric acid front three are added into 2000mL four-hole bottles
Ester, is cooled to -10～0 DEG C, Grignard reagent dropwise obtained in above-mentioned steps is entered in, be then heated to room
Temperature is simultaneously incubated 2h, after being then acidified with hydrochloric acid, washing layering, by organic layer vacuum distillation, residue crystallization
It is filtrated to get pentafluorophenyl boric acid solid 126g, yield 74%.
(3) 450mL glacial acetic acid is added into 1000mL four-hole bottles, stirring is opened, above-mentioned five are added
Fluorobenzoic boric acid solid 124g, dropwise addition hydrogen peroxide 81g (0.715mol) into bottle between 10 DEG C～15 DEG C,
Completion of dropping is incubated 6h, the hydrogen peroxide for then adding solution of sodium bisulfite destruction excessive into bottle, passes through
Distillation, rectifying obtain the white crystal 98g of main content >=99.5%, yield 90%, total recovery 66.6%.
Preparation method disclosed in two patents of the above is primarily present following technical problem：Oxidation reaction is having
Carry out in machine solvent, such as dichloroethanes and glacial acetic acid, high cost is unfriendly to environment, and yield is low,
It is not suitable for industrialized production.Above technical problem is urgently to be resolved hurrily.
The content of the invention
The technical problem to be solved existing is entered for raw material by pentafluorophenyl boric acid to overcome
Row oxidation reaction needs to carry out in organic solvent, and high cost is unfriendly to environment, and yield is low and not
Suitable for the defect of industrialized production etc., and provide a kind of preparation method of 2,3,4,5,6- Pentafluorophenols.This
The preparation method oxidation reaction of invention is carried out in water, and low cost is environmentally friendly, and reaction yield and
Purity is high, is more suitable for industrialized production.
The present invention mainly solves by the following technical programs above-mentioned technical problem.
The invention provides a kind of preparation method of 2,3,4,5,6- Pentafluorophenols, it comprises the following steps：Water
In, 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI) and hydrogen peroxide are carried out into oxidation reaction, make
Obtain the 2,3,4,5,6- Pentafluorophenols as shown in formula (VII)；
The preparation method of the described 2,3,4,5,6- Pentafluorophenols as shown in formula (VII) is preferably comprised down
Row step：Added in the mixed solution of 2,3,4,5,6- pentafluorophenyl boric acids of the Xiang Shuihe as shown in formula (VI)
Hydrogen oxide, carries out described oxidation reaction.The mode of described addition can be the conventional mode in this area,
Preferably it is added dropwise.The speed of described dropwise addition can be not especially limited, the temperature of general control reaction system
Degree is between 40 DEG C～80 DEG C, you can.Described hydrogen peroxide is preferably with the shape of aqueous hydrogen peroxide solution
Formula is participated in reaction, and the mass fraction of described aqueous hydrogen peroxide solution is preferably 5%～35%, more
It is goodly 10%～27.5%, it is total that described percentage refers to that the quality of hydrogen peroxide accounts for aqueous hydrogen peroxide solution
The percentage of quality.Described compound (VI) and the mol ratio of hydrogen peroxide can be such anti-for this area
Mol ratio that should be conventional, preferably 1:1～1:4, it is more preferably 1:1～1:2.The consumption of described water can
It is not especially limited, as long as not affecting the carrying out reacted, it is preferred that described water and compound (VI)
Mass ratio be 1:1～1:3.The temperature of described oxidation reaction can be the conventional volume temperature of the such reaction in this area
Degree, preferably 40～80 DEG C, be more preferably 60～80 DEG C.The process of described oxidation reaction can be according to
The conventional detection method in this area is monitored (such as TLC, HPLC or GC), typically with compound
(VI) as the terminal of reaction when disappearing.The time of described oxidation reaction is preferably 2～12 hours,
More preferably it is 2～6h.
The preparation method of described 2,3,4,5, the 6- Pentafluorophenols as shown in formula (VII), it is preferred that its
The following steps can also be further included：
(1) bromofluorobenzenes of 2,3,4,5,6- five as shown in formula (V) are carried out into grignard reaction as follows
The bromofluorobenzene RMgBrs of 2,3,4,5,6- five as shown in formula (Va) are obtained；
(2) in ether solvent, by RMgBr obtained in step (1) and B (OR)3Carry out following institute
The reaction shown, is obtained the compound as shown in formula (Vb)；Then under the action of an acid, following institute is carried out
The hydrolysis for showing, is obtained described 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI)；
B(OR)3Or in the compound as shown in formula (Vb), R is C1～C4Alkyl.
In R, described C1～C4Alkyl be preferably methyl (- CH3), ethyl (- CH2CH3)、
N-propyl (- CH2CH2CH3), isopropyl (- CH2(CH3)2), normal-butyl (- CH2CH2CH2CH3)、
Isobutyl group (- CH2CH(CH3)2) or the tert-butyl group (- CH (CH3)3)。
In step (1), described 2,3,4,5,6- five bromofluorobenzene RMgBrs as shown in formula (Va)
Preparation method can be the conventional method in this area, be preferably comprised the following steps：Under gas shield, by magnesium
(generally magnesium chips) and ether solvent mixture mix with compound (V), carry out described grignard anti-
Should.Wherein, the gas in described gas shield can be the conventional protective gas of the such reaction in this area,
Preferably nitrogen.The temperature of described mixing can be the conventional temperature of the such reaction mixing in this area, compared with
It is goodly 40 DEG C～50 DEG C.Described ether solvent can be the conventional ether solvent of the such reaction in this area,
One or more preferably in ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran and methyltetrahydrofuran,
More preferably it is tetrahydrofuran.Described magnesium is the conventional magnesium of the such reaction in this area, generally commercially available.
Described magnesium can be the conventional mol ratio of the such reaction in this area with the mol ratio of compound (V), preferably
Ground is 1.0:1～1.2:1.The consumption of described ether solvent can be not especially limited, as long as not affecting reaction
Carry out, it is preferred that described ether solvent is 20～30 with the mass ratio of magnesium:1 (such as 26.2:1).
The temperature of described grignard reaction can be the conventional temperature of the such reaction in this area, preferably 40 DEG C
～50 DEG C.The detection method that the process of described RMgBr reaction can typically adopt this area conventional is carried out
Monitoring.The time of described grignard reaction is preferably 3～5 hours.
In step (1), described 2,3,4,5,6- five bromofluorobenzene RMgBrs as shown in formula (Va)
In preparation method, it is preferred that compound (V) is added drop-wise in magnesium and ether solvent mixture.It is described
The speed of dropwise addition can be not especially limited, it is preferred that the temperature of control reaction system is at 40 DEG C～50 DEG C
Between, you can.
In step (2), the preparation side of described 2,3,4,5,6- pentafluorophenyl boric acids as shown in formula (VI)
Method is preferably comprised the following steps：Under gas shield, at a temperature of -10 DEG C～-5 DEG C, by step (1)
The reactant liquor after terminating is reacted, with B (OR)3Mix with the mixed solution of ether solvent, carry out described
Reaction, is obtained the compound as shown in formula (Vb)；It is not post-treated, directly under the action of an acid, enter
Row hydrolysis, is obtained 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI).Wherein, described gas
Gas in body protection can be the conventional protective gas of the such reaction in this area, preferably nitrogen.Institute
The ether solvent stated can be the conventional ether solvent of the such reaction in this area, preferably ether, methyl- tert
One or more in butyl ether, tetrahydrofuran and methyltetrahydrofuran, is more preferably tetrahydrofuran.Institute
The consumption of the ether solvent stated can be not especially limited, as long as not affecting reaction to carry out.Described change
Compound B (OR)3Can be the conventional mol ratio of the such reaction in this area with the mol ratio of compound (V), compared with
It is goodly 1:1～2:1, it is more preferably 1:1～1.4:1.Described B (OR)3With the mixed solution of ether solvent
In, described B (OR)3Can be not especially limited with magnitude relation with described ether solvent, as long as not
Reaction is affected to carry out, it is preferred that described B (OR)3It is with the mass ratio of described ether solvent
0.5:1～3:1.The temperature of described reaction can be the conventional temperature of the such reaction in this area, preferably -10 DEG C
～-5 DEG C.The detection method that the process of described reaction can typically adopt this area conventional is monitored.Institute
The time of the reaction stated is preferably 2～8 hours.Described acid can be the conventional acid of the such reaction in this area,
Preferably hydrochloric acid.The mass fraction of described hydrochloric acid can be the conventional mass fraction in this area, preferably
For 5%～15%, described percentage refers to that the quality of hydrochloric acid accounts for the percentage of aqueous hydrochloric acid solution gross mass.
Described sour consumption can be not especially limited, as long as guaranteeing that reaction system is acid condition.It is described
The temperature of hydrolysis can be the conventional temperature of the such reaction in this area, preferably 10 DEG C～30 DEG C.
The time of described hydrolysis can be that this area is such reacts conventional time, preferably 5～30min.
In a preferred embodiment of the present invention, in step (2), described as shown in formula (VI) 2,3,4,5,6-
The preparation method of pentafluorophenyl boric acid comprises the following steps：Under gas shield, at a temperature of -10 DEG C～-5 DEG C,
By B (OR)3It is added drop-wise in the reactant liquor after step (1) reaction terminates with the mixed solution of ether solvent,
Described reaction is carried out, the compound as shown in formula (Vb) is obtained；It is not post-treated, directly in acid
Under effect, be hydrolyzed reaction, and 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI) are obtained.
The preparation method of described 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI), preferably may be used also
Further include the operation for post-processing.The method and condition of described post processing can be the such reaction in this area
The method and condition of routine, in the present invention, is preferably comprised the following steps：After separation hydrolysis terminates
Reactant liquor water layer and organic layer, water layer with ether solvent extract, merge organic layer, remove solvent,
.In described post-processing operation, described ether solvent can be the conventional ether solvent in this area,
One or more preferably in ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran and methyltetrahydrofuran,
More preferably it is tetrahydrofuran.The method of described removing solvent can be the conventional method in this area, preferably
For vacuum distillation.The solvent of removing be ether solvent, recoverable.
It is to shorten the production cycle in a preferred embodiment of the present invention, it is described as shown in formula (VI)
In the preparation method of 2,3,4,5,6- pentafluorophenyl boric acids, after described post processing terminates, without the need for separating, directly
Follow-up oxidation reaction is carried out, 2,3,4,5, the 6- Pentafluorophenols as shown in formula (VII) are obtained.
The preparation method of described 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI), it is preferred that its
The following steps can also be further included：Under lewis acidic catalysis, by five fluorine as shown in formula (IV)
Benzene carries out bromination reaction with bromine, and described 2,3,4,5,6- five bromofluorobenzenes as shown in formula (V) are obtained；
The preparation method of the described bromofluorobenzenes of 2,3,4,5,6- five as shown in formula (V) is preferably comprised following
Step：In solvent-free, under lewis acidic catalysis, the phenyl-pentafluoride as shown in formula (IV) is entered with bromine
Row bromination reaction, is obtained described 2,3,4,5,6- five bromofluorobenzenes as shown in formula (V)；More preferably include
The following steps：In solvent-free, phenyl-pentafluoride and lewis acidic mixture are mixed with bromine, carried out described
Bromination reaction.The temperature of described mixing can be temperature conventional when the such reaction in this area mixes, preferably
Ground is 40 DEG C～45 DEG C.Described bromine is preferably dropped in phenyl-pentafluoride and lewis acidic mixture.Institute
The speed of the dropwise addition stated can be not especially limited, as long as not affecting reaction to carry out, preferably control anti-
The temperature of system is answered between 40 DEG C～45 DEG C.Described lewis acid can be the conventional Louis in this area
Acid, preferably alchlor.Described compound (IV) can be such for this area with the mol ratio of bromine
The conventional mol ratio of reaction, preferably 1:1～1:2.Described lewis acidic consumption can be this area
The conventional consumption of such reaction, it is preferred that it is 3 with the mol ratio of compound (IV):10～1:10.
The temperature of described bromination reaction can be the conventional temperature of the such reaction in this area, preferably 40 DEG C
～45 DEG C.The detection method that the process of described bromination reaction can typically adopt this area conventional is monitored,
As the terminal of reaction when typically being disappeared using compound (IV).The time of described bromination reaction is preferably
It it is more preferably 12～18 hours for 5～18 hours.
After described bromination reaction terminates, it is preferred that can also further include the operation for post-processing.It is described
Post processing method and condition can be the conventional method of the such reaction in this area and condition, be preferably comprised
The following steps：Reactant liquor after bromination reaction is terminated, mixes with sodium sulfite aqueous solution, separates organic
Layer and water layer, water layer is extracted with halogenated hydrocarbon solvent, merges organic layer, removes solvent, rectifying, you can.
Wherein, the concentration and consumption of described sodium sulfite aqueous solution can be not especially limited, as long as can remove
Bromination reaction terminate after reactant liquor in remaining bromine, obtain colourless mixed liquor, it is preferably described
The mass fraction of sodium sulfite aqueous solution is 5～40%, and described percentage refers to that the quality of sodium sulfite is accounted for
The percentage of sodium sulfite aqueous solution gross mass.Described halogenated hydrocarbon solvent can be this area extraction with often
The halogenated hydrocarbon solvent of rule, preferably dichloromethane.The method of described removing solvent can be this area
Conventional method, preferably reduced pressure concentration.The halogenated hydrocarbon solvent recoverable of removing.
The preparation method of described 2,3,4,5,6- five bromofluorobenzenes as shown in formula (V), it is preferred that may be used also
Further include the following steps：In amide solvent, by 2,3,4,5, the 6- phenyl-pentafluorides as shown in formula (III)
Formic acid carries out decarboxylic reaction as follows, and the described phenyl-pentafluoride as shown in formula (IV) is obtained；
In the preparation method of the described phenyl-pentafluoride as shown in formula (IV), the condition of described decarboxylic reaction
Can be that this area is such reacts conventional condition, the present invention preferably following condition：Described amide solvent
Preferably N,N-dimethylformamide.The temperature of described decarboxylic reaction is preferably 150～160 DEG C.
The detection method that the process of described decarboxylic reaction can typically adopt this area conventional be monitored, typically with
As the terminal of reaction when compound as shown in formula (III) disappears.
The preparation method of the described phenyl-pentafluoride as shown in formula (IV), after preferably can also further including
Process operation.The method and condition of described post-processing operation can be the conventional method of the such reaction in this area
And condition, it is preferred that after described decarboxylic reaction terminates, 85 DEG C～90 DEG C of cut is collected in rectifying,
Obtain final product the phenyl-pentafluoride as shown in formula (IV).
The preparation method of the described phenyl-pentafluoride as shown in formula (IV), it is preferred that can also further include
The following steps：In water, in the presence of sulfuric acid, by 2,3,4,5, the 6- phenyl-pentafluoride nitriles as shown in formula (II)
Hydrolysis as follows is carried out, described 2,3,4,5, the 6- phenyl-pentafluoride first as shown in formula (III) are obtained
Acid；
In the preparation method of described 2,3,4,5, the 6- pentafluoro benzoic acids as shown in formula (III), described water
The condition of solution reaction can be that this area is such reacts conventional condition, the present invention preferably following condition：It is described
The concentration of sulfuric acid can be the conventional concentration of the such reaction in this area, preferably mass fraction is 50～70%
Aqueous sulfuric acid, described percentage refers to that the quality of sulfuric acid accounts for the percentage of aqueous sulfuric acid gross mass.
The consumption of described sulfuric acid can be not especially limited, it is preferred that it is with the mol ratio of compound (II)
2:1～3:1.The temperature of described hydrolysis can be the conventional temperature in this area, preferably 150 DEG C
～170 DEG C.The consumption of described water can be not especially limited, as long as not affecting reaction to carry out, you can.Institute
The detection method that the process of the hydrolysis stated can typically adopt this area conventional be monitored (such as TLC,
HPLC or GC), as the terminal of reaction when typically being disappeared using the compound as shown in formula (II).Institute
The time of the hydrolysis stated is preferably 2～4 hours.
In the preparation method of described 2,3,4,5, the 6- pentafluoro benzoic acids as shown in formula (III), described water
After solution reaction terminates, it is preferred that can also further include the operation for post-processing.The side of described post processing
Method and condition can be the conventional method of the such reaction in this area and condition, be preferably comprised the following steps：Will
Hydrolysis terminate after reactant liquor, be cooled to room temperature, filter, be dried, you can.
The preparation method of described 2,3,4,5, the 6- pentafluoro benzoic acids as shown in formula (III), it is preferred that its
The following steps can also be further included：In organic solvent, in the presence of catalyst and dehydrating agent, will be as
2,3,4,5,6- Perchlorobenzonitriles shown in formula (I) carry out fluorination reaction as follows with KF, are obtained described
The 2,3,4,5,6- phenyl-pentafluoride nitriles as shown in formula (II)；
The preparation method of the described 2,3,4,5,6- phenyl-pentafluoride nitriles as shown in formula (II) is preferably comprised following
Step：By the mixed liquor of organic solvent, catalyst, dehydrating agent and KF, and as shown in formula (I)
2,3,4,5,6- Perchlorobenzonitriles mix, and carry out described fluorination reaction.Wherein, the temperature of described mixing can
For the conventional temperature of the such reaction in this area, preferably mix at a temperature of 200 DEG C～220 DEG C.It is described
Organic solvent can be the conventional organic solvent of the such reaction in this area, preferably sulfone class solvent, nitrile
One or more in solvent, ether solvent and ketones solvent.Described sulfone class preferred solvents ground is ring fourth
Sulfone.Described nitrile solvents are preferably benzonitrile.Described ether solvent is preferably diethylene glycol two
Methyl ether and/or tetraethyleneglycol dimethyl ether.Described ketones solvent is preferably 1,3- dimethyl-2-imidazolinones
And/or 1,3- DMPUs.Described catalyst can be the conventional catalyst of the such reaction in this area,
Preferably tetrabutyl phosphonium bromide phosphorus, tetraphenylphosphonium chloride, dibenzo 18- are preced with 6, calixarenes, poly- second two
One or more in alcohol and tetrabutyl ammonium fluoride, is more preferably tetrabutyl ammonium fluoride.Described dehydrating agent
Can be the conventional dehydrating agent of the such reaction in this area, preferably hexamethylene or toluene are more preferably toluene.
The consumption of described dehydrating agent can be not especially limited, and those skilled in the art are according to ordinary skill
Knowledge can determine that, it is preferred that described dehydrating agent is 0.1 with the mass ratio of compound (I):1～1:1,
More preferably it is 0.5:1～1:1.Described compound (I) can be the such reaction in this area with the mol ratio of KF
Conventional mol ratio, preferably 1:6～1:12, it is more preferably 1:8～1:10.The use of described catalyst
Amount can be that this area is such reacts conventional consumption, preferably the 2%～20% of compound (I) quality,
More preferably it is 2%～10%.The consumption of described dehydrating agent can be not especially limited, as long as will can react
Water removing in system is complete, you can.The consumption of described organic solvent can be not especially limited, as long as
Reaction is not affected to carry out, you can, preferably, it is 3 with the mass ratio of compound (I):1～6:1.Institute
The temperature of the fluorination reaction stated can be the conventional temperature of the such reaction in this area, preferably 200 DEG C
～220 DEG C.The detection method that the process of described fluorination reaction can typically adopt this area conventional is monitored,
As the terminal of reaction when the general compound using as shown in formula (I) disappears.Described fluorination reaction
Time is preferably 3～5 hours.
In the preparation method of described 2,3,4,5, the 6- phenyl-pentafluoride nitriles as shown in formula (II), it is preferred that will
After water removing completely in the mixed liquor of organic solvent, catalyst, dehydrating agent and KF, add such as formula
(I) the 2,3,4,5,6- Perchlorobenzonitriles shown in.The described 2,3,4,5,6- Perchlorobenzonitriles as shown in formula (I)
During reaction is preferably participated in the form of the organic solution of compound (I).Described compound (I)
Organic solution in, described compound (I) can be not especially limited with organic solvent with magnitude relation,
As long as not affecting reaction to carry out, you can.The mode of described addition can be the conventional mode in this area, compared with
It is goodly dropwise addition.The speed of described dropwise addition can be not especially limited, as long as not affecting reaction to carry out, i.e.,
Can, the speed of dropwise addition is usually in order to controlling reaction temperature is between 200 DEG C～220 DEG C.
In a preferred embodiment of the present invention, if described dehydrating agent can be described such as formula with recovery
(II) 2 shown in, in the preparation method of 3,4,5,6- phenyl-pentafluoride nitriles, it is preferred that by organic solvent, being catalyzed
After water removing completely in the mixed liquor of agent, dehydrating agent and KF, recovery dehydrating agent, add as
2,3,4,5,6- Perchlorobenzonitriles shown in formula (I).
In the preparation method of described 2,3,4,5, the 6- phenyl-pentafluoride nitriles as shown in formula (II), preferably adopt
The mode of operation of side border ring extraction, i.e., while fluorination reaction is carried out, produce (typically by rectifying
Mode produce, for example carry out in rectifying column) 2,3,4,5, the 6- phenyl-pentafluoride nitriles as shown in formula (II) (evaporate
Divide 160 DEG C～162 DEG C).The mode of operation of described side border ring extraction is preferably comprised the following steps：Will
After water removing completely in the mixed liquor of organic solvent, catalyst, dehydrating agent and KF, at 200 DEG C～220 DEG C
At a temperature of, the organic solution of 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I) is added dropwise, carry out described
Fluorination reaction, when the organic solution that 2,3,4,5,6- Perchlorobenzonitriles as shown in formula (I) are added dropwise
After 1/15～1/30 (time for adding is usually 5 minutes～15 minutes, such as 10 minutes), with volume or matter
Gauge, starts to produce 2,3,4,5, the 6- phenyl-pentafluoride nitriles (160 DEG C～162 DEG C of cut) as shown in formula (II)；
Up to the organic solution completion of dropping of 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I), fluorination reaction is entered
Row is complete.
Under normal circumstances, 2,3,4,5,6- phenyl-pentafluoride nitriles (160 DEG C of the cut in extraction as shown in formula (II)
～162 DEG C) when, according to common sense in the field, need for temperature of reaction system to be down to 160 DEG C～162 DEG C.Such as
The organic solution time for adding of the 2,3,4,5,6- Perchlorobenzonitriles shown in formula (I) is generally 3～5 hours.Such as
The extraction time of the 2,3,4,5,6- phenyl-pentafluoride nitriles shown in formula (II) is generally 3～5 hours.
In a preferred embodiment of the present invention, the mode of operation of described side border ring extraction is carrying rectifying
Carry out in the reactor of tower, for example the four-hole bottle with rectifying column.
Present invention also offers the preparation method of 2,3,4,5,6- pentafluorophenyl boric acids of the one kind as shown in formula (VI),
It comprises the following steps：
(1) bromofluorobenzenes of 2,3,4,5,6- five as shown in formula (V) are carried out into grignard reaction as follows
The bromofluorobenzene RMgBrs of 2,3,4,5,6- five as shown in formula (Va) are obtained；
(2) under gas shield, at a temperature of -10 DEG C～-5 DEG C, by B (OR)3It is mixed with ether solvent
Close solution to be added drop-wise in the reactant liquor after step (1) reaction terminates, carry out described reaction, be obtained such as
Compound shown in formula (Vb)；Not post-treated, directly under the action of an acid, be hydrolyzed reaction,
The 2,3,4,5,6- pentafluorophenyl boric acids as shown in formula (VI) are obtained；
B(OR)3Or in the compound as shown in formula (Vb), R is C1～C4Alkyl.
In R, described C1～C4Alkyl be preferably methyl (- CH3), ethyl (- CH2CH3)、
N-propyl (- CH2CH2CH3), isopropyl (- CH2(CH3)2), normal-butyl (- CH2CH2CH2CH3)、
Isobutyl group (- CH2CH(CH3)2) or the tert-butyl group (- CH (CH3)3)。
In step (1), described 2,3,4,5,6- five bromofluorobenzene RMgBrs as shown in formula (Va)
Preparation method can be the conventional method in this area, be preferably comprised the following steps：Under gas shield, by magnesium
(generally magnesium chips) and ether solvent mixture mix with compound (V), carry out described grignard anti-
Should.Wherein, the gas in described gas shield can be the conventional protective gas of the such reaction in this area,
Preferably nitrogen.The temperature of described mixing can be the conventional temperature of the such reaction mixing in this area, compared with
It is goodly 40 DEG C～50 DEG C.Described ether solvent can be the conventional ether solvent of the such reaction in this area,
One or more preferably in ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran and methyltetrahydrofuran,
More preferably it is tetrahydrofuran.Described magnesium is the conventional magnesium of the such reaction in this area, generally commercially available.
Described magnesium can be the conventional mol ratio of the such reaction in this area with the mol ratio of compound (V), preferably
Ground is 1.0:1～1.2:1.The consumption of described ether solvent can be not especially limited, as long as not affecting reaction
Carry out, it is preferred that described ether solvent is 20～30 with the mass ratio of magnesium:1 (such as 26.2:1).
The temperature of described grignard reaction can be the conventional temperature of the such reaction in this area, preferably 40 DEG C
～50 DEG C.The detection method that the process of described RMgBr reaction can typically adopt this area conventional is carried out
Monitoring.The time of described grignard reaction is preferably 3～5 hours.
In step (1), described 2,3,4,5,6- five bromofluorobenzene RMgBrs as shown in formula (Va)
In preparation method, it is preferred that compound (V) is added drop-wise in magnesium and ether solvent mixture.It is described
The speed of dropwise addition can be not especially limited, it is preferred that the temperature of control reaction system is at 40 DEG C～50 DEG C
Between, you can.
In step (2), the gas in described gas shield can be the conventional guarantor of the such reaction in this area
Shield property gas, preferably nitrogen.Described ether solvent can be the conventional ethers of the such reaction in this area
One kind in solvent, preferably ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran and methyltetrahydrofuran or
It is various, it is more preferably tetrahydrofuran.The consumption of described ether solvent can be not especially limited, as long as not
Reaction is affected to carry out.Described compound B (OR)3Can be ability with the mol ratio of compound (V)
The conventional mol ratio of the such reaction in domain, preferably 1:1～2:1, it is more preferably 1:1～1.4:1.Described
B(OR)3In the mixed solution of ether solvent, described B (OR)3With the consumption of described ether solvent
Relation can be not especially limited, as long as not affecting reaction to carry out, it is preferred that described B (OR)3
It is 0.5 with the mass ratio of described ether solvent:1～3:1.The temperature of described reaction can be such for this area
The conventional temperature of reaction, preferably -10 DEG C～-5 DEG C.The process of described reaction can typically adopt ability
The conventional detection method in domain is monitored.The time of described reaction is preferably 2～8 hours.Described
Acid can be the conventional acid of the such reaction in this area, preferably hydrochloric acid.The mass fraction of described hydrochloric acid can
For the conventional mass fraction in this area, preferably 5%～15%, described percentage refers to the matter of hydrochloric acid
Amount accounts for the percentage of aqueous hydrochloric acid solution gross mass.Described sour consumption can be not especially limited, as long as really
Guarantor's reaction system is acid condition.The temperature of described hydrolysis can be normal for the such reaction in this area
The temperature of rule, preferably 10 DEG C～30 DEG C.The time of described hydrolysis can be such anti-for this area
Answer conventional time, preferably 5～30min.
The preparation method of described 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI), preferably may be used also
Further include the operation for post-processing.The method and condition of described post processing can be the such reaction in this area
The method and condition of routine, in the present invention, is preferably comprised the following steps：After separation hydrolysis terminates
Reactant liquor water layer and organic layer, water layer with ether solvent extract, merge organic layer, remove solvent,
.In described post-processing operation, described ether solvent can be the conventional ether solvent in this area,
One or more preferably in ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran and methyltetrahydrofuran,
More preferably it is tetrahydrofuran.The method of described removing solvent can be the conventional method in this area, preferably
For vacuum distillation.The solvent of removing be ether solvent, recoverable.
Present invention also offers the preparation method of 2,3,4,5,6- five bromofluorobenzenes of the one kind as shown in formula (V),
It comprises the following steps：In solvent-free, under lewis acidic catalysis, will be as shown in formula (IV) five
Fluorobenzene carries out bromination reaction with bromine, and 2,3,4,5,6- five bromofluorobenzenes as shown in formula (V) are obtained；
The preparation method of the described bromofluorobenzenes of 2,3,4,5,6- five as shown in formula (V) is preferably comprised following
Step：In solvent-free, phenyl-pentafluoride and lewis acidic mixture are mixed with bromine, carry out described bromination
Reaction.The temperature of described mixing can be temperature conventional when the such reaction in this area mixes, preferably
40 DEG C～45 DEG C.Described bromine is preferably dropped in phenyl-pentafluoride and lewis acidic mixture.Described
The speed of dropwise addition can be not especially limited, as long as not affecting reaction to carry out, preferably control reactant
The temperature of system is between 40 DEG C～45 DEG C.Described lewis acid can be the conventional lewis acid in this area,
Preferably alchlor.Described compound (IV) can be the such reaction in this area with the mol ratio of bromine
Conventional mol ratio, preferably 1:1～1:2.Described lewis acidic consumption can be such for this area
The conventional consumption of reaction, it is preferred that it is 3 with the mol ratio of compound (IV):10～1:10.It is described
The temperature of bromination reaction can be the conventional temperature of the such reaction in this area, preferably 40 DEG C～45 DEG C.
The detection method that the process of described bromination reaction can typically adopt this area conventional be monitored, typically with
As the terminal of reaction when compound (IV) disappears.The time of described bromination reaction is preferably 5～18
Hour, it is more preferably 12～18 hours.
After described bromination reaction terminates, it is preferred that can also further include the operation for post-processing.It is described
Post processing method and condition can be the conventional method of the such reaction in this area and condition, be preferably comprised
The following steps：Reactant liquor after bromination reaction is terminated, mixes with sodium sulfite aqueous solution, separates organic
Layer and water layer, water layer is extracted with halogenated hydrocarbon solvent, merges organic layer, removes solvent, rectifying, you can.
Wherein, the concentration and consumption of described sodium sulfite aqueous solution can be not especially limited, as long as can remove
Bromination reaction terminate after reactant liquor in remaining bromine, obtain colourless mixed liquor, it is preferably described
The mass fraction of sodium sulfite aqueous solution is 5～40%, and described percentage refers to that the quality of sodium sulfite is accounted for
The percentage of sodium sulfite aqueous solution gross mass.Described halogenated hydrocarbon solvent can be this area extraction with often
The halogenated hydrocarbon solvent of rule, preferably dichloromethane.The method of described removing solvent can be this area
Conventional method, preferably reduced pressure concentration.The halogenated hydrocarbon solvent recoverable of removing.
Present invention also offers 2,3,4,5,6- phenyl-pentafluoride nitriles of the one kind as shown in formula (II), it includes following
Step：After by the water removing completely in the mixed liquor of organic solvent, catalyst, dehydrating agent and KF,
At a temperature of 200 DEG C～220 DEG C, the organic solution of 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I) is added dropwise,
Carry out described fluorination reaction；When the organic molten of 2,3,4,5,6- Perchlorobenzonitriles as shown in formula (I) is added dropwise
Behind the 1/15～1/30 of liquid, in terms of volume or quality, start to produce 2,3,4,5,6- as shown in formula (II)
Phenyl-pentafluoride nitrile；Until the organic solution completion of dropping of 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I),
Fluorination reaction is carried out completely；
In the preparation method of described 2,3,4,5, the 6- phenyl-pentafluoride nitriles as shown in formula (II), described is organic
Solvent can be the conventional organic solvent of the such reaction in this area, preferably sulfone class solvent, nitrile solvents,
One or more in ether solvent and ketones solvent.Described sulfone class preferred solvents ground is sulfolane.Institute
The nitrile solvents stated are preferably benzonitrile.Described ether solvent be preferably diethylene glycol dimethyl ether and
/ or tetraethyleneglycol dimethyl ether.Described ketones solvent be preferably 1,3- dimethyl-2-imidazolinones and/or
1,3- DMPUs.Described catalyst can be the conventional catalyst of the such reaction in this area, preferably
Ground for tetrabutyl phosphonium bromide phosphorus, tetraphenylphosphonium chloride, dibenzo 18- hat 6, calixarenes, polyethylene glycol and
One or more in tetrabutyl ammonium fluoride, is more preferably tetrabutyl ammonium fluoride.Described dehydrating agent can be
The conventional dehydrating agent of the such reaction in this area, preferably hexamethylene or toluene, are more preferably toluene.Institute
The consumption of the dehydrating agent stated can be not especially limited, and those skilled in the art know according to ordinary skill
Knowledge can determine that, it is preferred that described dehydrating agent is 0.1 with the mass ratio of compound (I):1～1:1,
More preferably it is 0.5:1～1:1.Described compound (I) can be the such reaction in this area with the mol ratio of KF
Conventional mol ratio, preferably 1:6～1:12, it is more preferably 1:8～1:10.The use of described catalyst
Amount can be that this area is such reacts conventional consumption, preferably the 2%～20% of compound (I) quality,
More preferably it is 2%～10%.The consumption of described dehydrating agent can be not especially limited, as long as will can react
Water removing in system is complete, you can.The consumption of described organic solvent can be not especially limited, as long as
Reaction is not affected to carry out, you can, preferably, it is 3 with the mass ratio of compound (I):1～6:1.Institute
The temperature of the fluorination reaction stated can be the conventional temperature of the such reaction in this area, preferably 200 DEG C
～220 DEG C.The detection method that the process of described fluorination reaction can typically adopt this area conventional is monitored,
As the terminal of reaction when the general compound using as shown in formula (I) disappears.Described fluorination reaction
Time is preferably 3～5 hours.
In the preparation method of described 2,3,4,5, the 6- phenyl-pentafluoride nitriles as shown in formula (II), it is preferred that institute
In the organic solution of the compound (I) stated, described compound (I) uses magnitude relation with organic solvent
Can be not especially limited, as long as not affecting reaction to carry out, you can.The speed of described dropwise addition can not be made to have
Body is limited, as long as not affecting reaction to carry out, you can, the speed of dropwise addition is usually for controlling reaction temperature
Between 200 DEG C～220 DEG C.
In a preferred embodiment of the present invention, if described dehydrating agent can be described such as formula with recovery
(II) 2 shown in, in the preparation method of 3,4,5,6- phenyl-pentafluoride nitriles, it is preferred that by organic solvent, being catalyzed
After water removing completely in the mixed liquor of agent, dehydrating agent and KF, recovery dehydrating agent, add as
2,3,4,5,6- Perchlorobenzonitriles shown in formula (I).
Under normal circumstances, 2,3,4,5,6- phenyl-pentafluoride nitriles (160 DEG C of the cut in extraction as shown in formula (II)
～162 DEG C) when, according to common sense in the field, need for temperature of reaction system to be down to 160 DEG C～162 DEG C.Such as
The organic solution time for adding of the 2,3,4,5,6- Perchlorobenzonitriles shown in formula (I) is generally 3～5 hours.Such as
The extraction time of the 2,3,4,5,6- phenyl-pentafluoride nitriles shown in formula (II) is generally 3～5 hours.
In a preferred embodiment of the present invention, the mode of operation of described side border ring extraction is carrying rectifying
Carry out in the reactor of tower, for example the four-hole bottle with rectifying column.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and obtain final product this
Invent each preferred embodiments.
Agents useful for same of the present invention and raw material are commercially available.
The present invention positive effect be：
(1) in the preparation method of 2,3,4,5,6- Pentafluorophenols of the present invention as shown in formula (VII), use
Water makees solvent, low cost, environmentally friendly, and reaction yield and purity are high, are more suitable for industrialization safety
Production.
(2) present invention is adopted in the preparation method of 2,3,4,5, the 6- phenyl-pentafluoride nitriles as shown in formula (II)
The mode of operation of side border ring extraction, can directly obtain target compound of the GC purity more than 99%,
Without the need for rectifying again.This processing mode can allow the concentration of target compound in reaction system maintain compared with
Low-level, plus the carrying out of fast response, the reaction time is shortened to 3～5 hours from 10h, is more suitable for industry
Metaplasia is produced.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but is not therefore limited the present invention to
Among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to normal
Rule method and condition, or select according to catalogue.
The preparation of the 2,3,4,5,6- phenyl-pentafluoride nitriles of embodiment 1
1,3- DMPU 1200g, potassium fluoride are put into four-hole bottles of the 2000mL with rectifying column
511.3g (8.8mol), tetrabutyl ammonium fluoride 11.5g (0.044mol) and toluene 200g.Temperature rising reflux
Band water, after band water is finished, by toluene recovery is steamed.Temperature is risen into 220 DEG C, high temperature is added dropwise
The mixing of 2,3,4,5,6- Perchlorobenzonitriles (300g, 1.1mol) and 1,3- DMPUs (300g) is molten
Liquid (hereinafter referred to as material), while be added dropwise while produce, start dropwise addition material 10min (about 1/18 material,
With initial material total volume meter), fluorination reaction is carried out, rectifying tower top temperature is begun to decline to 160～162 DEG C,
The cut (according to backflow situation) of slow 160～162 DEG C of extraction, until material dropping is finished, react into
Row is complete.Total time for adding is 3h, and the extraction time is 5h.Control produces cut at 160～162 DEG C, directly
Connect and obtain 2,3,4,5,6- phenyl-pentafluoride nitrile 192g, GC (gas-chromatography) purity assay is 99.2%, yield
90.4%.Target compound carries out GCMS analyses, and m/z=193.1 is defined as 2,3,4,5,6- phenyl-pentafluorides
Nitrile.
The preparation of the 2,3,4,5,6- phenyl-pentafluoride nitriles of embodiment 2
By embodiment 1, the amount of potassium fluoride is down into 383.5g (6.6mol) by 511.3g (8.8mol).
Catalyst uses dibenzo 18- hats 6 instead, and consumption is 15g, the product 175.8g that rectifying goes out when being added dropwise,
GC (gas-chromatography) purity assay is 99.4%, yield 82.8%.The same embodiment of GCMS analysis results
1。
The preparation of the 2,3,4,5,6- phenyl-pentafluoride nitriles of embodiment 3
By embodiment 1, the amount of potassium fluoride is risen into 639.1g (11mol) by 511.3g (8.8mol).
The product 178.34g that rectifying goes out when being added dropwise, GC (gas-chromatography) purity assay is 99.1%, yield
84.0%.GCMS analysis results are with embodiment 1.
The preparation of the 2,3,4,5,6- phenyl-pentafluoride nitriles of embodiment 4
By embodiment 1, the consumption of tetrabutyl ammonium fluoride is risen into 28.75g from 11.5g (0.044mol)
(0.11mol).The product 182.8g that goes out of rectifying when being added dropwise, GC (gas-chromatography) purity assay is
99.2%, yield 86.1%.GCMS analysis results are with embodiment 1.
The preparation of the 2,3,4,5,6- phenyl-pentafluoride nitriles of embodiment 5
By embodiment 1,1,3- DMPUs are substituted for into sulfolane.The product 172.8g for obtaining,
GC (gas-chromatography) purity assay is 99.4%, yield 81.4%.The same embodiment of GCMS analysis results
1。
The preparation of the 2,3,4,5,6- phenyl-pentafluoride nitriles of embodiment 6
By embodiment 1, temperature is substituted for into 200 DEG C by 220 DEG C.The product 154.4g for obtaining, GC (gas
Phase chromatogram) purity assay be 99.0%, yield 72.7%.GCMS analysis results are with embodiment 1.
The preparation of the 2,3,4,5,6- pentafluoro benzoic acids of embodiment 7
70% aqueous sulfuric acid 1251.6g (8.94mol) and 2,3,4,5,6- is added in 2000mL four-hole bottles
Phenyl-pentafluoride nitrile 700g (3.62mol), is warming up to 155 DEG C, is incubated 2h, is cooled to 20～25 DEG C, mistake
Filter drying obtains 2,3,4,5,6- pentafluoro benzoic acid 684.1g, HPLC (high performance liquid chromatography) purity 99.0%,
Yield 95.3%.13C NMR(CDCl3)δ:107(C1, s), 136.7～139.0,139.1～139.4 (C3,5,
m),142.9(C4, s), 145.0～145.5,147.6～147.7 (C2,6,m),164.2(CO,s)。
The preparation of the 2,3,4,5,6- pentafluoro benzoic acids of embodiment 8
50% aqueous sulfuric acid 1419.04g (7.24mol) and 2,3,4,5,6- is added in 3000mL four-hole bottles
Phenyl-pentafluoride nitrile 700g (3.62mol), is warming up to 170 DEG C, is incubated 4h, is cooled to 20～25 DEG C, mistake
Filter drying obtains 2,3,4,5,6- pentafluoro benzoic acid 677.7g, HPLC (high performance liquid chromatography) purity 99.0%,
Yield 94.4%.Carbon modal data is with embodiment 7.
The preparation of the 2,3,4,5,6- phenyl-pentafluorides of embodiment 9
DMF 600g and 2,3,4,5,6- pentafluoro benzoic acids are added in the band rectifying column four-hole bottle of 1000mL
300g (1.51mol), is warming up to 160 DEG C, and flow back 2h, and reaction terminates, and starts to produce (rectifying),
Reflux ratio 2:1, the cut of 85～90 DEG C of top temperature is collected, it is phenyl-pentafluoride, obtain phenyl-pentafluoride 240.3g, GC
(gas-chromatography) purity assay 99.5%, yield 94.4%, GCMS analyses, m/z=168.0, it is determined that
Generate 2,3,4,5,6- phenyl-pentafluorides.
The preparation of the bromofluorobenzenes of 10 2,3,4,5,6- of embodiment five
336g (2mol) phenyl-pentafluoride, 40g (0.3mol) trichlorine are added in the four-hole bottle of 1000mL
Change aluminium, reactant is heated into 45 DEG C under stirring, be slowly added dropwise 320g (2mol) bromine, mixture
18h is stirred at being maintained at 45 DEG C, insulation adds 10% sodium sulfite 200g, stirs to system after finishing
It is colourless, oil reservoir is separated, water layer is extracted with dichloromethane 50g × 2, merges organic phase, steams dichloro
Methane recovery is applied mechanically, and concentrate rectifying obtains five bromofluorobenzene 447.1g, content 99.5%, yield 90.5%.
Target compound carries out GCMS analyses, and m/z=245.9 is defined as 2,3,4,5,6- five bromofluorobenzenes.
The preparation of the bromofluorobenzenes of 11 2,3,4,5,6- of embodiment five
336g (2mol) phenyl-pentafluoride, 26.67g (0.2mol) three are added in the four-hole bottle of 1000mL
Aluminium chloride, 45 DEG C are heated under stirring by reactant, are slowly added dropwise 640g (4mol) bromine, mixing
Thing stirs 12h at being maintained at 45 DEG C, insulation adds 10% sodium sulfite 200g, stirs to body after finishing
It is colourless, separates oil reservoir, water layer is extracted with dichloromethane 50g × 2, merges organic phase, steams two
Chloromethanes recovery, concentrate rectifying obtains five bromofluorobenzene 442.9g, content 99.4%, yield 89.6%.
GCMS analysis results are with embodiment 10.
The preparation of the 2,3,4,5,6- pentafluorophenyl boric acids of embodiment 12
The addition magnesium chips 26.7g and tetrahydrofuran 700g in 2000mL four-hole bottles, nitrogen displacement 3 times,
40～45 DEG C are warming up to, 2,3,4,5,6- five bromofluorobenzene 247g (1.0mol) are added dropwise, be incubated at 40～45 DEG C,
Total time is added dropwise and be incubated for 5h, 2,3,4,5,6- five bromofluorobenzene RMgBrs are obtained.
RMgBr is cooled under nitrogen protection -5 DEG C, to system be added dropwise trimethylborate (119.5g,
1.15mol) with tetrahydrofuran (120g) mixed liquor, Bi Baowen 2h are dripped, after insulation terminates, will be reacted
Drop is added in 15% watery hydrochloric acid (540g), after stirring 30min, separates water layer, water layer tetrahydrochysene furan
Mutter 200g × 3 extraction.Merge organic layer and obtain 2,3,4,5,6- pentafluorophenyl boric acid tetrahydrofuran solution 1450g,
Content 13.2%, yield 90.33%.19F NMR(400MHz,DMSO)δ:-137.94(s,2F),
-153.61(s,1F),-161.30(s,2F).1H NMR(400MHz,DMSO)δ:6.87(s,2H)。
The preparation of the 2,3,4,5,6- pentafluorophenyl boric acids of embodiment 13
The addition magnesium chips 24g and methyltetrahydrofuran 720g in 2000mL four-hole bottles, nitrogen displacement 3 times,
50 DEG C are warming up to, 2,3,4,5,6- five bromofluorobenzene 247g (1.0mol) are added dropwise, in 50 DEG C of insulations, be added dropwise
It is 3h with insulation total time, obtains 2,3,4,5,6- five bromofluorobenzene RMgBrs.
RMgBr is cooled under nitrogen protection -10 DEG C, tri-n-butyl borate is added dropwise to system
(322.22g, 1.4mol) and methyltetrahydrofuran (120g) mixed liquor, drips Bi Baowen 8h, insulation
After end, reactant liquor is added drop-wise in 15% watery hydrochloric acid (540g), after stirring 30min, separates water layer,
Water layer is extracted with methyltetrahydrofuran 200g × 3.Merge organic layer and obtain 2,3,4,5,6- pentafluorophenyl boric acid first
Base tetrahydrofuran solution 1451g, content 13.0%, yield 89.02%.Fluorine modal data and hydrogen modal data are same
Embodiment 12.
The preparation of the 2,3,4,5,6- Pentafluorophenols of embodiment 14
2,3,4,5,6- penta phenyl fluoride boron acid solution tetrahydrofuran solutions are added in the four-hole bottle of 2000mL
1450g (0.933mol), decompression steams tetrahydrofuran recycling, and in four mouthfuls batches distilled water is added
600g, is warming up to 70 DEG C, and 27.5% hydrogen peroxide 161.5g (1.30mol) is added dropwise, and protects after completion of dropping
Temperature, time for adding and temperature retention time are combined into 3 hours, after insulation is finished, are down to room temperature, filter, filter cake
With 30g × 2 eluent methylene chloride, filtrate is extracted with 150g dichloromethane, and organic phase is merged after extraction.
Dichloromethane recovery is steamed, concentrate vacuum distillation obtains 2,3,4,5,6- Pentafluorophenol 161.6g, GC
(gas-chromatography) content 99.8%, yield 94.1%.Target compound carries out GCMS analyses,
M/z=184.1, is defined as 2,3,4,5,6- Pentafluorophenols.
The preparation of the 2,3,4,5,6- Pentafluorophenols of embodiment 15
By embodiment 14, reaction temperature is substituted for into 40 DEG C by 70 DEG C, hydrogen peroxide concentration is by 27.5% drop
For 10%, consumption is changed to 380.8g (1.12mol), and reaction is complete, the product 158.3g that rectifying goes out,
GC (gas-chromatography) purity assay is 99.5%, yield 92.2%.The same embodiment of GCMS analysis results
14。
The preparation of the 2,3,4,5,6- Pentafluorophenols of embodiment 16
By embodiment 14, reaction temperature is substituted for into 80 DEG C by 70 DEG C, time for adding and temperature retention time are prolonged
6h is grown to, reaction is complete, the product 159.8g that rectifying goes out, GC (gas-chromatography) purity assay is 99.6%,
Yield 93.1%.GCMS analysis results are with embodiment 14.
Claims (17)
1. one kind 2, the preparation method of 3,4,5,6- Pentafluorophenols, it is characterised in that it comprises the following steps：
In water, 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI) and hydrogen peroxide are carried out into oxidation reaction,
The 2,3,4,5,6- Pentafluorophenols as shown in formula (VII) are obtained；
2. preparation method as claimed in claim 1, it is characterised in that described such as formula (VII) institute
The preparation method of the 2,3,4,5,6- Pentafluorophenols for showing comprises the following steps：Xiang Shuihe is as shown in formula (VI)
Hydrogen peroxide is added in the mixed solution of 2,3,4,5,6- pentafluorophenyl boric acids, described oxidation reaction is carried out；Its
In, the mode of described addition is preferably added dropwise；Described hydrogen peroxide is preferably with aquae hydrogenii dioxidi
The form of solution is participated in reaction, and the mass fraction of described aqueous hydrogen peroxide solution is preferably
5%～35%, it is more preferably 10%～27.5%；Described compound (VI) and the mol ratio of hydrogen peroxide
Preferably 1:1～1:4, it is more preferably 1:1～1:2；Described water is with the mass ratio of compound (VI)
Preferably 1:1～1:3；The temperature of described oxidation reaction is preferably 40 DEG C～80 DEG C, is more preferably 60 DEG C
～80 DEG C；The time of described oxidation reaction is preferably 2～12 hours, is more preferably 2～6h.
3. preparation method as claimed in claim 1 or 2, it is characterised in that described such as formula (VII)
The preparation method of shown 2,3,4,5,6- Pentafluorophenols still further comprises the following steps：
(1) bromofluorobenzenes of 2,3,4,5,6- five as shown in formula (V) are carried out into grignard reaction as follows
The bromofluorobenzene RMgBrs of 2,3,4,5,6- five as shown in formula (Va) are obtained；
(2) in ether solvent, by RMgBr obtained in step (1) and B (OR)3Carry out following institute
The reaction shown, is obtained the compound as shown in formula (Vb)；Then under the action of an acid, following institute is carried out
The hydrolysis for showing, is obtained described 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI)；
B(OR)3Or in the compound as shown in formula (Vb), R is C1～C4Alkyl.
4. preparation method as claimed in claim 3, it is characterised in that in R, described C1～C4
Alkyl be methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or the tert-butyl group；
And/or, in step (1), described 2,3,4,5, the 6- five bromofluorobenzene grignard as shown in formula (Va)
The preparation method of reagent comprises the following steps：Under gas shield, by magnesium and ether solvent mixture and chemical combination
Thing (V) mixes, and carries out described grignard reaction；Wherein, the gas in described gas shield is preferable
Ground is nitrogen；The temperature of described mixing is preferably 40 DEG C～50 DEG C；Described ether solvent is preferably
For one or more in ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran and methyltetrahydrofuran；Described
Magnesium is preferably 1.0 with the mol ratio of compound (V):1～1.2:1；The matter of described ether solvent and magnesium
Amount ratio preferably 20:1～30:1；The temperature of described grignard reaction is preferably 40 DEG C～50 DEG C；It is described
Time of grignard reaction be preferably 3～5 hours；
And/or, in step (2), described 2,3,4,5,6- pentafluorophenyl boric acids as shown in formula (VI)
Preparation method comprises the following steps：Under gas shield, at a temperature of -10 DEG C～-5 DEG C, by step (1)
The reactant liquor after terminating is reacted, with B (OR)3Mix with the mixed solution of ether solvent, carry out described
Reaction, is obtained the compound as shown in formula (Vb)；It is not post-treated, directly under the action of an acid, enter
Row hydrolysis, is obtained 2,3,4,5, the 6- pentafluorophenyl boric acids as shown in formula (VI)；Wherein, described gas
Gas in body protection is preferably nitrogen；Described ether solvent is preferably ether, methyl tertbutyl
One or more in ether, tetrahydrofuran and methyltetrahydrofuran；Described compound B (OR)3With change
The mol ratio of compound (V) is preferably 1:1～2:1, it is more preferably 1:1～1.4:1；The temperature of described reaction
Preferably -10 DEG C～-5 DEG C of degree；The time of described reaction is preferably 2～8 hours；Described acid compared with
It is goodly hydrochloric acid；The mass fraction of described hydrochloric acid is preferably 5%～15%；Described hydrolysis
Temperature is preferably 10 DEG C～30 DEG C；The time of described hydrolysis is preferably 5～30min.
5. preparation method as claimed in claim 4, it is characterised in that
In step (1), described 2,3,4,5,6- five bromofluorobenzene RMgBrs as shown in formula (Va)
In preparation method, compound (V) is added drop-wise in magnesium and ether solvent mixture；
And/or, in step (2), described 2,3,4,5,6- pentafluorophenyl boric acids as shown in formula (VI)
In preparation method, by B (OR)3It is added drop-wise in step (1) reactant liquor with the mixed solution of ether solvent；
And/or, in the preparation method of described 2,3,4,5,6- pentafluorophenyl boric acids as shown in formula (VI),
After described post processing terminates, without the need for separating, follow-up oxidation reaction is directly carried out, be obtained such as formula (VII)
Shown 2,3,4,5,6- Pentafluorophenols.
6. preparation method as claimed in claim 3, it is characterised in that described such as formula (VI) institute
The preparation method of the 2,3,4,5,6- pentafluorophenyl boric acids for showing still further comprises the following steps：Lewis acidic
Under catalysis, the phenyl-pentafluoride as shown in formula (IV) and bromine are carried out into bromination reaction, be obtained described such as formula (V)
The shown bromofluorobenzenes of 2,3,4,5,6- five；
7. preparation method as claimed in claim 6, it is characterised in that described as shown in formula (V)
The preparation method of the bromofluorobenzenes of 2,3,4,5,6- five comprise the following steps：In solvent-free, urge lewis acidic
Under change, the phenyl-pentafluoride as shown in formula (IV) and bromine are carried out into bromination reaction, be obtained described such as formula (V)
The shown bromofluorobenzenes of 2,3,4,5,6- five；It is preferably comprised the following steps：In solvent-free, by phenyl-pentafluoride and road
The mixture of Lewis acid mixes with bromine, carries out described bromination reaction；Wherein, the temperature of described mixing
Preferably 40 DEG C～45 DEG C；Described lewis acid is preferably alchlor；Described compound (IV)
1 is preferably with the mol ratio of bromine:1～1:2；The mol ratio of described lewis acid and compound (IV)
For 3:10～1:10；The temperature of described bromination reaction is preferably 40 DEG C～45 DEG C；Described bromination reaction
Time be preferably 5～18 hours, be more preferably 12～18 hours.
8. preparation method as claimed in claim 6, it is characterised in that described as shown in formula (V)
The preparation method of the bromofluorobenzenes of 2,3,4,5,6- five still further comprise the following steps：In amide solvent, will
2,3,4,5, the 6- pentafluoro benzoic acids as shown in formula (III) carry out decarboxylic reaction as follows, are obtained described
The phenyl-pentafluoride as shown in formula (IV)；
9. preparation method as claimed in claim 8, it is characterised in that described such as formula (IV) institute
In the preparation method of the phenyl-pentafluoride for showing, described amide solvent is DMF；And/or,
The temperature of described decarboxylic reaction is 150～160 DEG C.
10. preparation method as claimed in claim 8, it is characterised in that described such as formula (IV) institute
The preparation method of the phenyl-pentafluoride for showing still further comprises the following steps：In the presence of sulfuric acid, will be such as formula (II)
Shown 2,3,4,5,6- phenyl-pentafluoride nitriles carry out hydrolysis as follows, are obtained described such as formula (III)
Shown 2,3,4,5,6- pentafluoro benzoic acids；
11. preparation methods as claimed in claim 10, it is characterised in that described such as formula (III)
Shown 2, in the preparation method of 3,4,5,6- pentafluoro benzoic acids, described sulfuric acid is for mass fraction
50%～70% aqueous sulfuric acid；And/or, described sulfuric acid and the mol ratio of compound (II) is 2:1～3:1；
And/or, the temperature of described hydrolysis is 150 DEG C～170 DEG C；And/or, described hydrolysis
Time is 2～4 hours.
12. preparation methods as claimed in claim 10, it is characterised in that described such as formula (III)
The preparation method of shown 2,3,4,5,6- pentafluoro benzoic acids still further comprises the following steps：In organic solvent,
In the presence of catalyst and dehydrating agent, 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I) are entered with KF
Row fluorination reaction as follows, is obtained described 2,3,4,5, the 6- phenyl-pentafluoride nitriles as shown in formula (II)；
13. preparation methods as claimed in claim 12, it is characterised in that described such as formula (II) institute
The preparation method of the 2,3,4,5,6- phenyl-pentafluoride nitriles for showing comprises the following steps：By organic solvent, catalyst, take off
The mixed liquor of aqua and KF, mixes with 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I), carries out described
Fluorination reaction；Wherein, the temperature of described mixing preferably mixes at a temperature of 200 DEG C～220 DEG C；
Described organic solvent is preferably in sulfone class solvent, nitrile solvents, ether solvent and ketones solvent
Plant or various；Described sulfone class preferred solvents ground is sulfolane；Described nitrile solvents are preferably benzene first
Nitrile；Described ether solvent is preferably diethylene glycol dimethyl ether and/or tetraethyleneglycol dimethyl ether；Described
Ketones solvent is preferably 1,3- dimethyl-2-imidazolinones and/or 1,3- DMPUs；Described urges
Agent is preferably tetrabutyl phosphonium bromide phosphorus, tetraphenylphosphonium chloride, dibenzo 18- and is preced with 6, calixarenes, gathers
One or more in ethylene glycol and tetrabutyl ammonium fluoride；Described dehydrating agent is preferably hexamethylene or first
Benzene；Described dehydrating agent is preferably 0.1 with the mass ratio of compound (I):1～1:1；Described chemical combination
Thing (I) is preferably 1 with the mol ratio of KF:6～1:12, it is more preferably 1:8～1:10；Described catalysis
The better quality ground of agent is the 2%～20% of compound (I) quality, is more preferably 2%～10%；Described
Organic solvent is 3 with the mass ratio of compound (I):1～6:1；The temperature of described fluorination reaction is preferably
For 200 DEG C～220 DEG C；The time of described fluorination reaction is preferably 3～5 hours.
14. preparation methods as claimed in claim 13, it is characterised in that described such as formula (II) institute
2 for showing, in the preparation method of 3,4,5,6- phenyl-pentafluoride nitriles, by organic solvent, catalyst, dehydrating agent and KF
Mixed liquor in water removing completely after, add 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I)；
And/or, in the preparation method of described 2,3,4,5,6- phenyl-pentafluoride nitriles as shown in formula (II), adopt
The mode of operation of side border ring extraction, i.e., while fluorination reaction is carried out, produce as shown in formula (II)
2,3,4,5,6- phenyl-pentafluoride nitriles；The mode of operation of described side border ring extraction is preferably comprised the following steps：
After by the water removing completely in the mixed liquor of organic solvent, catalyst, dehydrating agent and KF, at 200 DEG C
At a temperature of～220 DEG C, the organic solution of 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I) is added dropwise, is entered
The described fluorination reaction of row；When the organic solution that the 2,3,4,5,6- Perchlorobenzonitriles as shown in formula (I) are added dropwise
1/15～1/30 after, in terms of volume or quality, start to produce 2,3,4,5,6- five as shown in formula (II)
Fluorobenzonitrile；Until the organic solution completion of dropping of 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I), institute
The fluorination reaction stated is carried out completely.
The preparation method of 2,3,4,5,6- pentafluorophenyl boric acids of 15. one kind as shown in formula (VI), its feature exists
Comprise the following steps in it：
(1) bromofluorobenzenes of 2,3,4,5,6- five as shown in formula (V) are carried out into grignard reaction as follows
The bromofluorobenzene RMgBrs of 2,3,4,5,6- five as shown in formula (Va) are obtained；
(2) under gas shield, at a temperature of -10 DEG C～-5 DEG C, by B (OR)3It is mixed with ether solvent
Close solution to be added drop-wise in the reactant liquor after step (1) reaction terminates, carry out described reaction, be obtained such as
Compound shown in formula (Vb)；Not post-treated, directly under the action of an acid, be hydrolyzed reaction,
The 2,3,4,5,6- pentafluorophenyl boric acids as shown in formula (VI) are obtained；
B(OR)3Or in the compound as shown in formula (Vb), the definition of R, step (1) such as formula (Va)
Each condition and step (2) such as formula (VI) of the preparation method of the shown bromofluorobenzene RMgBrs of 2,3,4,5,6- five
Each condition of the preparation method of shown 2,3,4,5,6- pentafluorophenyl boric acids is with any one of claim 3～5 institute
State.
The preparation method of 2,3,4,5,6- five bromofluorobenzenes of 16. one kind as shown in formula (V), it is characterised in that
It comprises the following steps：In solvent-free, under lewis acidic catalysis, will be as shown in formula (IV) five
Fluorobenzene carries out bromination reaction with bromine, and 2,3,4,5,6- five bromofluorobenzenes as shown in formula (V) are obtained；
Wherein, each condition of the preparation method of described 2,3,4,5,6- five bromofluorobenzenes as shown in formula (V)
With described in claim 7.
2,3,4,5,6- phenyl-pentafluoride nitriles of 17. one kind as shown in formula (II), it is characterised in that it includes following
Step：After by the water removing completely in the mixed liquor of organic solvent, catalyst, dehydrating agent and KF,
At a temperature of 200 DEG C～220 DEG C, the organic solution of 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I) is added dropwise,
Carry out described fluorination reaction；When the organic molten of 2,3,4,5,6- Perchlorobenzonitriles as shown in formula (I) is added dropwise
Behind the 1/15～1/30 of liquid, in terms of volume or quality, start to produce 2,3,4,5,6- as shown in formula (II)
Phenyl-pentafluoride nitrile；Until the organic solution completion of dropping of 2,3,4,5, the 6- Perchlorobenzonitriles as shown in formula (I),
Fluorination reaction is carried out completely；
Wherein, each condition of described 2,3,4,5, the 6- phenyl-pentafluoride nitrile preparation methods as shown in formula (II) is same
Described in claim 13.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106966871A (en) * | 2017-03-30 | 2017-07-21 | 大连奇凯医药科技有限公司 | A kind of preparation method of Pentafluorophenol |
| CN109503636A (en) * | 2018-12-11 | 2019-03-22 | 杭州澳赛诺生物科技有限公司 | A kind of synthetic method of 2,4,6- trifluoromethyl phenol |
| EP3696156A1 (en) | 2019-02-15 | 2020-08-19 | Fujian Yongjing Technology Co., Ltd. | New process for the manufacture of fluoroaryl compounds and derivatives |
| CN112442058A (en) * | 2020-12-04 | 2021-03-05 | 阜新睿光氟化学有限公司 | Preparation method of pentafluorophenylboronic acid |
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2015
- 2015-11-05 CN CN201510746066.XA patent/CN106673964A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106966871A (en) * | 2017-03-30 | 2017-07-21 | 大连奇凯医药科技有限公司 | A kind of preparation method of Pentafluorophenol |
| CN106966871B (en) * | 2017-03-30 | 2020-04-14 | 大连奇凯医药科技有限公司 | Preparation method of pentafluorophenol |
| CN109503636A (en) * | 2018-12-11 | 2019-03-22 | 杭州澳赛诺生物科技有限公司 | A kind of synthetic method of 2,4,6- trifluoromethyl phenol |
| EP3696156A1 (en) | 2019-02-15 | 2020-08-19 | Fujian Yongjing Technology Co., Ltd. | New process for the manufacture of fluoroaryl compounds and derivatives |
| US11420917B2 (en) | 2019-02-15 | 2022-08-23 | Fujian Yongjing Technology Co., Ltd. | Process for the manufacture of fluoroaryl compounds and derivatives |
| CN112442058A (en) * | 2020-12-04 | 2021-03-05 | 阜新睿光氟化学有限公司 | Preparation method of pentafluorophenylboronic acid |
| CN112442058B (en) * | 2020-12-04 | 2022-06-21 | 阜新睿光氟化学有限公司 | Preparation method of pentafluorophenylboronic acid |
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