CN115260009B - Preparation method of m-fluorophenol - Google Patents
Preparation method of m-fluorophenol Download PDFInfo
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- CN115260009B CN115260009B CN202110473313.9A CN202110473313A CN115260009B CN 115260009 B CN115260009 B CN 115260009B CN 202110473313 A CN202110473313 A CN 202110473313A CN 115260009 B CN115260009 B CN 115260009B
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- fluorophenol
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- alkali
- difluorobenzonitrile
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- SJTBRFHBXDZMPS-UHFFFAOYSA-N 3-fluorophenol Chemical compound OC1=CC=CC(F)=C1 SJTBRFHBXDZMPS-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- BNBRIFIJRKJGEI-UHFFFAOYSA-N 2,6-difluorobenzonitrile Chemical compound FC1=CC=CC(F)=C1C#N BNBRIFIJRKJGEI-UHFFFAOYSA-N 0.000 claims abstract description 51
- 239000003513 alkali Substances 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims description 134
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 117
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- 239000007788 liquid Substances 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 28
- 229910052708 sodium Inorganic materials 0.000 claims description 24
- 239000011734 sodium Substances 0.000 claims description 24
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 23
- 239000004299 sodium benzoate Substances 0.000 claims description 17
- 235000010234 sodium benzoate Nutrition 0.000 claims description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 13
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 12
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 33
- 238000003756 stirring Methods 0.000 description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 19
- 239000007864 aqueous solution Substances 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 12
- 239000012295 chemical reaction liquid Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000011521 glass Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- -1 for example Chemical compound 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- OPRAEULMWQJWHU-UHFFFAOYSA-N FC=1C=C(C=CC1)O.[Na] Chemical compound FC=1C=C(C=CC1)O.[Na] OPRAEULMWQJWHU-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WFRFIWOYBKTDII-UHFFFAOYSA-N 1,5-difluorocyclohexa-2,4-dien-1-ol Chemical compound FC1(CC(=CC=C1)F)O WFRFIWOYBKTDII-UHFFFAOYSA-N 0.000 description 1
- PQTOMFUBZUAPPS-UHFFFAOYSA-N 1,5-difluorocyclohexa-2,4-diene-1-carbonitrile Chemical compound FC1(CC(=CC=C1)F)C#N PQTOMFUBZUAPPS-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- MGNPLIACIXIYJE-UHFFFAOYSA-N n-fluoroaniline Chemical compound FNC1=CC=CC=C1 MGNPLIACIXIYJE-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
-
- 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
- C07C37/64—Preparation of O-metal compounds with O-metal group bound to a carbon atom belonging to a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to a preparation method of m-fluorophenol, belongs to the technical field of chemical synthesis, and solves the problems that raw materials are expensive and industrial production is difficult when m-fluorophenol is obtained by diazotizing and hydrolyzing m-difluorobenzene in the prior art. The method comprises the following steps: the m-fluorophenol is prepared by taking 2, 6-difluorobenzonitrile and alkali as raw materials. The technical scheme provided by the application can simplify the process, reduce the cost and improve the product yield.
Description
Technical Field
The application relates to the technical field of chemical synthesis, in particular to a preparation method of m-fluorophenol.
Background
M-fluorophenol is commonly used as an intermediate for medicines, pesticides, and dyes. The preparation of m-fluorophenol in the prior art is generally carried out by two methods:
1. the m-fluorophenol is obtained by diazotizing and hydrolyzing m-fluoroaniline, for example, m-fluoroaniline and concentrated sulfuric acid (30 wt% -60 wt%) are subjected to diazotizing reaction in a diazotizing kettle, and then hydrolysis is carried out in a hydrolyzing kettle.
2. The m-fluorophenol is obtained by hydrolyzing m-difluorobenzene, for example, by hydrolyzing m-difluorobenzene as a starting material under alkaline conditions.
The starting materials of the two methods, namely m-fluoroaniline and m-difluorophenol, have higher prices, and the two preparation processes are complex to operate and have harsh conditions, so that the two preparation processes are not industrially produced at present and are difficult to obtain.
Disclosure of Invention
In view of the above analysis, an embodiment of the present application is directed to a method for preparing m-fluorophenol, so as to solve at least one problem in the prior art.
The application aims at realizing the following technical scheme:
the embodiment of the application provides a preparation method of m-fluorophenol, which comprises the following steps:
the m-fluorophenol is prepared by taking 2, 6-difluorobenzonitrile and alkali as raw materials.
Further, 2, 6-difluorobenzonitrile and alkali are used as raw materials, water is used as a solvent to prepare sodium m-fluorophenol, and the sodium m-fluorophenol is neutralized with acid to obtain m-fluorophenol, wherein the alkali is water-soluble hydroxide.
Further, 2, 6-difluorobenzonitrile reacts with alkali to obtain 2, 6-difluorosodium benzoate, 2, 6-difluorosodium benzoate reacts with alkali to obtain 2-fluoro-6-hydroxy sodium benzoate, 2-fluoro-6-hydroxy sodium benzoate reacts with alkali to obtain sodium m-fluorophenol, and sodium m-fluorophenol reacts with acid to obtain m-fluorophenol.
Further, the 2, 6-difluorobenzonitrile reacts with alkali to form a first reaction process, and a first intermediate liquid containing 2, 6-difluorosodium benzoate is obtained;
the 2, 6-difluoro sodium benzoate reacts with alkali to form a second reaction process, and a second intermediate liquid containing 2-fluoro-6-hydroxy sodium benzoate is obtained;
the reaction of the 2-fluoro-6-hydroxy sodium benzoate and alkali is a third reaction process, so as to obtain a third intermediate liquid containing sodium m-fluorophenol;
and the reaction of sodium metafluorophenol and acid is a fourth reaction process, so that liquid containing metafluorophenol is obtained, and the liquid is extracted to obtain metafluorophenol.
Further, the molar ratio of the 2, 6-difluorobenzonitrile to the base is 1:4-1:4.5.
Further, the first reaction process includes:
heating and refluxing for 2.5-3.5 h, and absorbing reaction tail gas by water.
Further, the fourth reaction process includes:
and (3) regulating the pH value of the reaction liquid obtained in the third reaction process to 2-3 by using hydrochloric acid, extracting twice by using a mixed solvent of dichloromethane and ethyl acetate with the volume ratio of 2:1-2.5:1, merging an oil layer, and washing the oil layer by using sodium bicarbonate.
Further, the second reaction process and the third reaction process are performed simultaneously in the same reactor; the reaction conditions are that the reaction pressure is 0.3MPa to 1.0MPa, the reaction temperature is 140 ℃ to 180 ℃ and the reaction time is 4 hours to 8 hours.
Further, the first, second and third reaction processes are performed in a reactor having a reflux device, and the first reaction process is performed first, and then the second and third reaction processes are performed.
The application can at least realize one of the following beneficial effects:
1. the application provides a new path for preparing m-fluorophenol, which is characterized in that a designed reaction path is that 2, 6-difluorobenzonitrile is subjected to hydrolysis reaction to obtain 2, 6-difluorosodium benzoate, 2, 6-difluorosodium benzoate is subjected to substitution reaction to obtain 2-fluoro-6-hydroxy sodium benzoate, the 2-fluoro-6-hydroxy sodium benzoate is subjected to heating decarboxylation to obtain m-fluorophenol sodium salt, and the m-fluorophenol sodium salt is subjected to neutralization reaction to obtain m-fluorophenol, namely, the 2, 6-difluorobenzonitrile is subjected to hydrolysis reaction, substitution reaction, decarboxylation reaction and neutralization reaction to prepare the m-fluorophenol. Compared with m-fluorophenol obtained by diazotizing and hydrolyzing m-fluoroaniline, the method has the advantages of mild reaction conditions, safe and simple operation.
2. The application prepares the m-fluorophenol by taking the 2, 6-difluorobenzonitrile as the raw material, the 2, 6-difluorobenzonitrile can be produced in large scale in industry, and compared with the prior art which utilizes m-fluoroaniline and m-difluorobenzonitrile as the raw materials to prepare the m-fluorophenol, the reaction raw materials are easier to obtain, the application has larger economic advantage, and the production cost can be obviously reduced.
3. The hydrolysis reaction, substitution reaction and decarboxylation reaction of the 2, 6-difluorosodium benzoate can be carried out in the same reaction kettle, any intermediate product separation is not needed in the middle, the preparation process is simpler, the operability is strong, and compared with the preparation method in the prior art, the method has higher product yield.
In the application, the technical schemes can be mutually combined to realize more preferable combination schemes. Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the application. The objectives and other advantages of the application may be realized and attained by the embodiments of the application particularly pointed out in the written description and drawings.
Drawings
The drawings are only for purposes of illustrating particular embodiments and are not to be construed as limiting the application, like reference numerals being used to refer to like parts throughout the several views.
FIG. 1 is a nuclear magnetic spectrum of m-fluorophenol provided by an embodiment of the application.
Detailed Description
The following detailed description of preferred embodiments of the application is made in connection with the accompanying drawings, which form a part hereof, and together with the description of the embodiments of the application, are used to explain the principles of the application and are not intended to limit the scope of the application.
In the prior art, the main methods for preparing m-fluorophenol are diazotizing and hydrolyzing m-fluoroaniline to obtain m-fluorophenol and hydrolyzing m-difluorobenzene to obtain m-fluorophenol.
In the method for obtaining m-fluorophenol by diazotizing and hydrolyzing m-fluoroaniline, because diazo is unstable, the reaction condition needs to be strictly controlled in the process of diazotizing and treating the diazo, and the material and the performance of the reactor are required to be high, for example, a special diazotizing kettle is required in diazotizing.
In the method for obtaining m-fluorophenol by hydrolysis of m-difluorobenzene, because m-difluorobenzene is insoluble in water, m-difluorobenzene is difficult to hydrolyze under alkaline conditions and byproducts are more. It is often desirable to add an organic solvent to facilitate the reaction, for example, dimethyl sulfoxide may be added to reduce by-products of the reaction. Because of the existence of the water phase and the organic solvent phase in the reaction process, the stirring speed needs to be controlled, and once the stirring equipment is in a problem, the whole reaction yield is very low, and even the m-fluorophenol cannot be obtained. In addition, organic solvents such as dimethyl sulfoxide generally pose a major hazard to the human body or the environment.
In order to overcome the technical problems, the application selects 2, 6-difluorobenzonitrile as a raw material to prepare m-fluorophenol. The preparation of m-fluorophenol by using 2, 6-difluorobenzonitrile as a raw material has the following effects:
the first, 2, 6-difluorobenzonitrile is more readily available than m-fluoroaniline and m-difluorobenzene, and therefore can save production costs.
And reacting the second, 2, 6-difluorobenzonitrile with a base to obtain m-fluorophenol, thereby avoiding the preparation of m-fluorophenol by diazotization.
And the third, 2, 6-difluorobenzonitrile contains cyano, and the water solubility of the cyano is far greater than that of m-difluorobenzene, so that the 2, 6-difluorobenzonitrile is easier to hydrolyze, has fewer side reactions and does not need to add an organic solvent. The yield of the reaction is not dependent on the stirring speed.
Further, in the embodiment of the application, the specific technical concept of preparing the m-fluorophenol from the 2, 6-difluorobenzonitrile is as follows:
the first reaction process, 2, 6-difluorobenzonitrile reacts with alkali to obtain 2, 6-difluorosodium benzoate;
the second reaction process, 2, 6-difluoro sodium benzoate reacts with alkali to obtain 2-fluoro-6-hydroxy sodium benzoate;
in the third reaction process, 2-fluoro-6-hydroxy sodium benzoate reacts with alkali to obtain sodium metafluorophenol;
and in the fourth reaction process, the sodium m-fluorophenol reacts with acid to obtain m-fluorophenol.
Wherein, the alkali in the first reaction process, the second reaction process and the third reaction process are all water-soluble hydroxides, which are all the same, partially the same, completely different or partially different.
Specifically, the first reaction process converts the cyano group of the 2, 6-difluorobenzonitrile into the carboxyl group, and the water solubility of the reactant is further increased, so that the problem that the fluorine atom is difficult to replace by the hydroxyl group due to poor water solubility of the m-difluorobenzene is solved. In addition, the carboxyl group is an electron withdrawing group which can facilitate hydrolysis of the ortho halogen fluoride. The reaction conditions of the second reaction process, the third reaction process and the fourth reaction process are easy to control, the requirements on equipment are low, and the problems of complex equipment and complex process in the process of preparing m-fluorophenol by diazotization are solved. In addition, hydroxide ions are active in the second reaction process and the third reaction process, and hydroxide ions are generated after the hydroxide with good water solubility is dissolved in an aqueous solution, so that the second reaction process and the third reaction process can be simultaneously performed in the same reactor. Similarly, the first reaction process, the second reaction process and the third reaction process can be performed in the same reactor, but since the first reaction process needs to be performed under reflux conditions, the first reaction process, the second reaction process and the third reaction process can be performed in the same reactor with a reflux device, and the first reaction process is performed first, and then the second reaction process and the third reaction process are performed simultaneously. In the manner, the embodiment of the application further simplifies the process conditions and the process equipment.
For example, sodium hydroxide or potassium hydroxide may be used as a base in both the second reaction process and the third reaction process, and in this case, the second reaction process and the third reaction process may be carried out in an autoclave. The first reaction process, the second reaction process and the third reaction process can adopt sodium hydroxide or potassium hydroxide as alkali so as to facilitate the addition of the alkali required by the three reaction processes at one time during feeding, thereby reducing the feeding times. And meanwhile, the first reaction process, the second reaction process and the third reaction process are also convenient to react in the same reactor. It should be noted that, if the pressure of the reaction vessel is increased during the first reaction process, ammonia gas is not normally discharged, and thus a byproduct containing an amino group is formed. In order to avoid the above problems, it is necessary to perform the first reaction process under normal pressure reflux conditions so that the generated ammonia gas is discharged from the reactor, and then to simultaneously perform the reactions in the second reaction process and the third reaction process under high pressure and heating conditions. Since the first reaction process requires reflux, the first reaction process, the second reaction process, and the third reaction process are performed in the same reactor, and the reactor is required to have a reflux device.
In the embodiment of the application, the following conditions are selected for the alkali:
1. the alkali is hydroxide, and the alkali is not weaker than sodium hydroxide;
2. the alkali has better solubility in water.
Wherein, the condition 1 provides hydroxyl for the reaction, and ensures that the product is m-fluorophenol. Condition 2 ensures the concentration of hydroxyl in the aqueous solution, thereby ensuring that fluorine atoms on the benzene ring are preferentially replaced by hydroxyl groups, and reducing the probability of other groups replacing fluorine atoms on the benzene ring, so as to improve the reaction yield. For example, ammonia gas is generated during the first reaction, and because ammonia gas is extremely soluble in water, a certain amount of ammonia gas remains in water even in a heated reflux state, and these remaining ammonia gas molecules may possibly replace fluorine atoms on the benzene ring. At this time, if the alkali has a good solubility in water, the hydroxide in the aqueous solution is absolutely dominant in concentration, so that the fluorine atom on the benzene ring is preferentially substituted with the hydroxyl group, thereby reducing by-products.
Furthermore, condition 2 is a necessary condition for realizing the one-pot method, i.e., the first reaction process, the second reaction process and the third reaction process are performed in the same reactor. The three reaction processes all consume alkali, so that the realization of the one-pot method needs to add enough alkali before the reaction starts, for example, the alkali with the molar quantity of 3 to 5 times of 2, 6-difluorobenzonitrile is added in the first reaction process, the mass percent of the alkali in the aqueous solution is not less than 20 percent, and the alkali needs to have better water solubility.
Taking 2, 6-difluorobenzonitrile and sodium hydroxide as raw materials to prepare m-fluorophenol as an example, the embodiment of the application provides a preparation method of m-fluorophenol, which comprises the following steps:
step 1, heating and refluxing 2.5h-3.5h (2.5 h,2.6h,2.7h,2.8h,2.9h,3.0h,3.1h,3.2h,3.3h,3.4 h) of 2, 6-difluorobenzonitrile and sodium hydroxide in water, and absorbing reaction tail gas by using water to obtain a first intermediate liquid containing 2, 6-difluorobenzobenzoate.
And 2, obtaining the second intermediate liquid containing 2-fluoro-6-hydroxy sodium benzoate under the conditions that the pressure of the 2, 6-difluoro sodium benzoate and sodium hydroxide in the first intermediate liquid is 0.3MPa-1.0MPa (0.3 MPa,0.4MPa,0.5MPa,0.6MPa,0.8MPa,0.9MPa and 1.0 MPa) and the temperature is 140 ℃ -180 ℃ (145 ℃,150 ℃,155 ℃,160 ℃,165 ℃,170 ℃ and 175 ℃).
And 3, obtaining a third intermediate liquid containing sodium m-fluorophenol under the conditions that the pressure of the sodium 2-fluoro-6-hydroxy benzoate and sodium hydroxide in the second intermediate liquid is 0.3MPa-1.0MPa and the temperature is 140-180 ℃.
In the embodiment of the application, the corresponding reaction processes of the step 2 and the step 3 are performed simultaneously, so that the total time of the two steps is 4-8 h.
And 4, reacting sodium m-fluorophenol in the third intermediate liquid with acid, and extracting to obtain m-fluorophenol.
In the embodiment of the application, the specific process of post-treatment is as follows: adjusting the pH value of the reaction liquid obtained in the third step to 2-3 by hydrochloric acid, wherein the volume ratio is 2:1 with ethyl acetate, combining the oil layers, and washing the oil layers with baking soda.
The mechanism of the above process is as follows:
from the above reaction mechanism, the first intermediate liquid is an aqueous solution containing sodium 2-fluoro-6-hydroxy benzoate, the second intermediate liquid is an aqueous solution containing sodium 2-fluoro-6-hydroxy benzoate, and the third intermediate liquid is an aqueous solution containing sodium m-fluorophenol salt.
To illustrate the feasibility of the above embodiments, the embodiments of the application provide the following examples:
example 1
139 g of 2, 6-difluorobenzonitrile, 640 g of water and 160 g of sodium hydroxide (the molar ratio of the 2, 6-difluorobenzonitrile to the sodium hydroxide is 1:4 and the mass percent of the sodium hydroxide in the aqueous solution is 20%) are put into a one-liter glass flask, heated, stirred and refluxed for 3 hours, and ammonia gas generated by the reaction is absorbed by water.
Pouring the reaction liquid into an autoclave, heating to 150 ℃, keeping the temperature and stirring for 4 hours, increasing the pressure in the autoclave to 0.4MPa, and cooling overnight.
The reaction solution in the autoclave was poured into a 2 l beaker, neutralized to ph=3 with hydrochloric acid under stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol 82 g is obtained through vacuum rectification. The yield thereof was found to be 73%. The gas phase content is >99%.
Example 2
139 g of 2, 6-difluorobenzonitrile, 480 g of water and 120 g of sodium hydroxide (the molar ratio of the 2, 6-difluorobenzonitrile to the sodium hydroxide is 1:3 and the mass percent of the sodium hydroxide in the aqueous solution is 20%) are put into a one-liter glass flask, heated, stirred and refluxed for 3 hours, and ammonia gas generated by the reaction is absorbed by water.
Pouring the reaction liquid into an autoclave, heating to 150 ℃, keeping the temperature and stirring for 4 hours, increasing the pressure in the autoclave to 0.4MPa, and cooling overnight.
The reaction solution in the autoclave was poured into a 2 l beaker, neutralized to ph=3 with hydrochloric acid under stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol is obtained by decompression rectification, 68 g. The yield thereof was found to be 55%. The gas phase content is >99%.
Example 3
139 g of 2, 6-difluorobenzonitrile, 640 g of water and 160 g of sodium hydroxide (the molar ratio of the 2, 6-difluorobenzonitrile to the sodium hydroxide is 1:4 and the mass percent of the sodium hydroxide in the aqueous solution is 20%) are put into a one-liter glass flask, heated, stirred and refluxed for 3 hours, and ammonia gas generated by the reaction is absorbed by water.
Pouring the reaction liquid into an autoclave, heating to 150 ℃, keeping the temperature and stirring for 6 hours, increasing the pressure in the autoclave to 0.4MPa, and cooling overnight.
The reaction solution in the autoclave was poured into a 2 l beaker, neutralized to ph=3 with hydrochloric acid under stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid of m-fluorophenol 91 g is obtained through vacuum rectification. The yield thereof was found to be 81%. The gas phase content is more than 99 percent
Example 4
139 g of 2, 6-difluorobenzonitrile, 640 g of water and 160 g of sodium hydroxide (the molar ratio of the 2, 6-difluorobenzonitrile to the sodium hydroxide is 1:4 and the mass percent of the sodium hydroxide in the aqueous solution is 20%) are put into a one-liter glass flask, heated, stirred and refluxed for 3 hours, and ammonia gas generated by the reaction is absorbed by water.
Pouring the reaction liquid into an autoclave, heating to 150 ℃, preserving heat and stirring for 8 hours, increasing the pressure in the autoclave to 0.4MPa, and cooling overnight.
The reaction solution in the autoclave was poured into a 2 l beaker, neutralized to ph=3 with hydrochloric acid under stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol 92 g is obtained through vacuum rectification. The yield thereof was found to be 82%. The gas phase content is >99%.
Example 5
139 g of 2, 6-difluorobenzonitrile, 640 g of water and 160 g of sodium hydroxide (the molar ratio of the 2, 6-difluorobenzonitrile to the sodium hydroxide is 1:4 and the mass percent of the sodium hydroxide in the aqueous solution is 20%) are put into the reactor, and the mixture is heated, stirred and refluxed for 3 hours, and the reaction is carried out to generate ammonia which is absorbed by water.
Heated to 150 degrees and stirred for 8 hours with heat preservation, the pressure in the reactor was increased to 0.4MPa and cooled overnight.
The reaction solution in the reactor was poured into a 2 l beaker, neutralized with hydrochloric acid to ph=3 with stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol 92 g is obtained through vacuum rectification. The yield thereof was found to be 82%. The gas phase content is >99%.
Example 6
139 g of 2, 6-difluorobenzonitrile, 896 g of water and 224 g of potassium hydroxide (the molar ratio of the 2, 6-difluorobenzonitrile to the potassium hydroxide is 1:4, and the mass percent of the potassium hydroxide in the aqueous solution is 20%) are put into a one-liter glass flask, heated, stirred and refluxed for 3 hours, and ammonia gas generated by the reaction is absorbed by water.
Pouring the reaction liquid into an autoclave, heating to 150 ℃, preserving heat and stirring for 8 hours, increasing the pressure in the autoclave to 0.4MPa, and cooling overnight.
The reaction solution in the autoclave was poured into a 2 l beaker, neutralized to ph=3 with hydrochloric acid under stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol 92 g is obtained through vacuum rectification. The yield thereof was found to be 82%. The gas phase content is >99%.
Example 7
139 g of 2, 6-difluorobenzonitrile, 896 g of water and 224 g of potassium hydroxide (the mol ratio of the 2, 6-difluorobenzonitrile to the potassium hydroxide is 1:4, and the mass percent of the potassium hydroxide in the aqueous solution is 20%) are put into the reactor, and the mixture is heated, stirred and refluxed for 3 hours, and ammonia gas generated by the reaction is absorbed by water.
Heated to 150 degrees and stirred for 8 hours with heat preservation, the pressure in the reactor was increased to 0.4MPa and cooled overnight.
The reaction solution in the reactor was poured into a 2 l beaker, neutralized with hydrochloric acid to ph=3 with stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol 92 g is obtained through vacuum rectification. The yield thereof was found to be 82%. The gas phase content is >99%.
Example 8
Into a one liter glass flask, 139 g of 2, 6-difluorobenzonitrile, 656 g of water and 164 g of sodium hydroxide (the molar ratio of the 2, 6-difluorobenzonitrile to the sodium hydroxide is 1:4.1, and the mass percent of the sodium hydroxide in the aqueous solution is 20%) are put, and the mixture is heated, stirred and refluxed for 2.6 hours, and the reaction is carried out to generate ammonia which is absorbed by water.
Pouring the reaction liquid into an autoclave, heating to 145 ℃, preserving heat and stirring for 5 hours, increasing the pressure in the autoclave to 0.5MPa, and cooling overnight.
The reaction solution in the autoclave was poured into a 2 l beaker, neutralized to ph=3 with hydrochloric acid under stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol 82 g is obtained through vacuum rectification. The yield thereof was found to be 80%. The gas phase content is >99%.
Example 9
Into a one liter glass flask, 139 g of 2, 6-difluorobenzonitrile, 692 g of water and 168 g of sodium hydroxide (the molar ratio of the 2, 6-difluorobenzonitrile to the sodium hydroxide is 1:4.2, and the mass percent of the sodium hydroxide in the aqueous solution is 20%) were put, and the mixture was heated, stirred and refluxed for 2.8 hours, and the reaction product was absorbed by water.
Pouring the reaction liquid into an autoclave, heating to 150 ℃, preserving heat and stirring for 7 hours, increasing the pressure in the autoclave to 0.6MPa, and cooling overnight.
The reaction solution in the autoclave was poured into a 2 l beaker, neutralized to ph=3 with hydrochloric acid under stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol 83 g is obtained through vacuum rectification. The yield thereof was found to be 81%. The gas phase content is >99%.
Example 10
139 g of 2, 6-difluorobenzonitrile, 698 g of water and 172 g of sodium hydroxide (the mol ratio of the 2, 6-difluorobenzonitrile to the sodium hydroxide is 1:4.3, and the mass percent of the sodium hydroxide in the aqueous solution is 20%) are put into a one-liter glass flask, and the mixture is heated, stirred and refluxed for 3.2 hours, and ammonia gas generated by the reaction is absorbed by water.
Pouring the reaction liquid into an autoclave, heating to 160 ℃, preserving heat and stirring for 7 hours, increasing the pressure in the autoclave to 0.6MPa, and cooling overnight.
The reaction solution in the autoclave was poured into a 2 l beaker, neutralized to ph=3 with hydrochloric acid under stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol 83 g is obtained through vacuum rectification. The yield thereof was found to be 81.3%. The gas phase content is >99%.
Example 11
Into a one liter glass flask, 139 g of 2, 6-difluorobenzonitrile, 704 g of water and 176 g of sodium hydroxide (the molar ratio of the 2, 6-difluorobenzonitrile to the sodium hydroxide is 1:4.4, and the mass percent of the sodium hydroxide in the aqueous solution is 20%) are put, and the mixture is heated, stirred and refluxed for 3.4 hours, and the reaction is carried out to generate ammonia which is absorbed by water.
Pouring the reaction liquid into an autoclave, heating to 170 ℃, preserving heat and stirring for 8 hours, increasing the pressure in the autoclave to 0.8MPa, and cooling overnight.
The reaction solution in the autoclave was poured into a 2 l beaker, neutralized to ph=3 with hydrochloric acid under stirring, extracted twice with 200ML of a mixed solvent of dichloromethane and ethyl acetate (volume ratio of dichloromethane to ethyl acetate: 2:1), the oil layers were combined and washed with 50 ML of 5% baking soda.
The solvent is recovered from the oil layer at normal pressure, and then the colorless transparent liquid m-fluorophenol is obtained by vacuum rectification, 85 g. The yield thereof was found to be 81.5%. The gas phase content is >99%.
The nuclear magnetic patterns of examples 1-11 are shown in FIG. 1, with DMSO as the deuterating agent.
The molar ratio of 2, 6-difluorobenzonitrile to sodium hydroxide in example 1 was 1:4 and the product yield was 73%, while the molar ratio of 2, 6-difluorobenzonitrile to sodium hydroxide in example 2 was 1:3 and the product yield was 55%, indicating that the higher the initial amount of sodium hydroxide, the more thorough the reaction in the examples of the present application.
In example 1, the high pressure reaction was carried out at a product yield of 73% for 4 hours, in example 3, the high pressure reaction was carried out at a product yield of 81% for 6 hours, and in example 3, the high pressure reaction was carried out at a product yield of 82% for 8 hours. In the examples of the present application, the high pressure is helpful for the reaction.
Example 4 the procedure for obtaining sodium m-fluorophenol was carried out in a beaker and autoclave respectively with a product yield of 82% and example 5 the procedure for obtaining sodium m-fluorophenol was carried out in one reactor only with a product yield of 82%. The three-step reaction involved in the process of obtaining the sodium metafluorophenol can be truly realized by a one-pot method, so that the process is simplified.
Example 6 the procedure for obtaining sodium m-fluorophenol when the base is potassium hydroxide was carried out in a beaker and autoclave, respectively. In example 7, where the base is potassium hydroxide, the process for obtaining sodium m-fluorophenol is carried out in only one reactor, and the product yields of both examples are 82%, indicating that potassium hydroxide can replace sodium hydroxide.
Examples 1-11 illustrate that the reactions provided by the examples of the present application can all occur under the reaction conditions provided by the examples of the present application.
Furthermore, the cost of the intermediate fluoroaniline in the prior art is 1296 yuan/100 g, the cost of m-difluorobenzene 189 yuan/100 g, and the cost of 2, 6-difluorobenzonitrile is 15.5 yuan/100 g.
In summary, the application uses 2, 6-difluorobenzonitrile as raw material, all reactions can be carried out in the same reaction kettle without separation in the middle, and the raw material price is much lower than that of m-fluoroaniline and m-difluorobenzene used in the prior art, and the application has the characteristics of low cost and simple process.
The above is only a preferred embodiment of the present application, but the scope of the present application is not limited thereto. Any changes or substitutions that would be readily apparent to one skilled in the art within the scope of the present disclosure are intended to be encompassed within the scope of the present application.
Claims (4)
1. A method for preparing m-fluorophenol, comprising: 2, 6-difluorobenzonitrile and alkali are heated and refluxed for 2.5-3.5 hours, reaction tail gas is absorbed by water, 2, 6-difluorosodium benzoate is obtained by reaction, 2, 6-difluorosodium benzoate and alkali react under the condition that the pressure is 0.3MPa-1.0MPa and the temperature is 140-180 ℃ to obtain 2-fluoro-6-hydroxy sodium benzoate, and 2-fluoro-6-hydroxy sodium benzoate and alkali react under the condition that the pressure is 0.3MPa-1.0MPa and the temperature is 140-180 ℃ to obtain sodium m-fluorophenol, and sodium m-fluorophenol reacts with acid to obtain m-fluorophenol;
the method comprises the steps of adjusting the pH value of sodium metafluorophenol to 2-3 by hydrochloric acid, extracting twice by using a mixed solvent of dichloromethane and ethyl acetate with the volume ratio of 2:1, merging an oil layer, and washing the oil layer by using sodium bicarbonate to obtain metafluorophenol;
the preparation process of the m-fluorophenol involves the following equation:
；
wherein the alkali is sodium hydroxide, and the molar ratio of the 2, 6-difluorobenzonitrile to the alkali is 1:4-1:4.5.
2. The method of manufacturing according to claim 1, comprising:
the 2, 6-difluorobenzonitrile reacts with alkali to form a first reaction process, and a first intermediate liquid containing 2, 6-difluorosodium benzoate is obtained;
the 2, 6-difluoro sodium benzoate reacts with alkali to form a second reaction process, and a second intermediate liquid containing 2-fluoro-6-hydroxy sodium benzoate is obtained;
the reaction of the 2-fluoro-6-hydroxy sodium benzoate and alkali is a third reaction process, so as to obtain a third intermediate liquid containing sodium m-fluorophenol;
and the reaction of sodium metafluorophenol and acid is a fourth reaction process, so that liquid containing metafluorophenol is obtained, and the liquid is extracted to obtain metafluorophenol.
3. The method according to claim 2, wherein,
the second reaction process and the third reaction process are performed simultaneously in the same reactor; the reaction conditions are that the reaction pressure is 0.3MPa to 1.0MPa, the temperature is 140 ℃ to 180 ℃ and the reaction time is 4 hours to 8 hours.
4. A process according to claim 3, wherein,
the first, second and third reaction processes are performed in a reactor having a reflux device, and the first reaction process is performed first, and then the second and third reaction processes are performed.
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