CN116514662A - Preparation method of 5-fluoro-2-nitrophenol - Google Patents
Preparation method of 5-fluoro-2-nitrophenol Download PDFInfo
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- CN116514662A CN116514662A CN202211593001.2A CN202211593001A CN116514662A CN 116514662 A CN116514662 A CN 116514662A CN 202211593001 A CN202211593001 A CN 202211593001A CN 116514662 A CN116514662 A CN 116514662A
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- QQURWFRNETXFTN-UHFFFAOYSA-N 5-fluoro-2-nitrophenol Chemical compound OC1=CC(F)=CC=C1[N+]([O-])=O QQURWFRNETXFTN-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 76
- 239000007787 solid Substances 0.000 claims abstract description 72
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 46
- RJXOVESYJFXCGI-UHFFFAOYSA-N 2,4-difluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1F RJXOVESYJFXCGI-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000003513 alkali Substances 0.000 claims abstract description 38
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 28
- 239000002994 raw material Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000012074 organic phase Substances 0.000 claims abstract description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 20
- 239000001110 calcium chloride Substances 0.000 claims abstract description 14
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 14
- 239000006184 cosolvent Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 13
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims abstract description 9
- 229910001634 calcium fluoride Inorganic materials 0.000 claims abstract description 9
- -1 fluoride ions Chemical class 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 230000033444 hydroxylation Effects 0.000 claims abstract description 5
- 238000005805 hydroxylation reaction Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 99
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 62
- 239000000047 product Substances 0.000 claims description 55
- 239000012071 phase Substances 0.000 claims description 31
- 239000000706 filtrate Substances 0.000 claims description 18
- 230000001105 regulatory effect Effects 0.000 claims description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- 239000012065 filter cake Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 238000002386 leaching Methods 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 4
- 238000004064 recycling Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 8
- 230000007062 hydrolysis Effects 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 6
- 238000007086 side reaction Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000010025 steaming Methods 0.000 abstract description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 32
- 239000012535 impurity Substances 0.000 description 19
- 239000007791 liquid phase Substances 0.000 description 18
- 239000010410 layer Substances 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000002699 waste material Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 6
- 230000036632 reaction speed Effects 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 5
- 239000011775 sodium fluoride Substances 0.000 description 5
- 235000013024 sodium fluoride Nutrition 0.000 description 5
- 239000002351 wastewater Substances 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 4
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 238000010587 phase diagram Methods 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- PEDMFCHWOVJDNW-UHFFFAOYSA-N 5-fluoro-2-nitroaniline Chemical compound NC1=CC(F)=CC=C1[N+]([O-])=O PEDMFCHWOVJDNW-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- FOUWCSDKDDHKQP-UHFFFAOYSA-N flumioxazin Chemical compound FC1=CC=2OCC(=O)N(CC#C)C=2C=C1N(C1=O)C(=O)C2=C1CCCC2 FOUWCSDKDDHKQP-UHFFFAOYSA-N 0.000 description 2
- 230000002363 herbicidal effect Effects 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- SJTBRFHBXDZMPS-UHFFFAOYSA-N 3-fluorophenol Chemical compound OC1=CC=CC(F)=C1 SJTBRFHBXDZMPS-UHFFFAOYSA-N 0.000 description 1
- 229910004261 CaF 2 Inorganic materials 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/16—Separation; Purification; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of organic synthesis, and relates to a preparation method of 5-fluoro-2-nitrophenol, which takes 2, 4-difluoronitrobenzene as a raw material, takes a nonpolar organic solvent as a solvent, takes solid alkali as a hydroxylation reagent, and takes dimethyl sulfoxide as a solid alkali cosolvent to prepare the 5-fluoro-2-nitrophenol. The system adopts a nonpolar organic solvent, and the reaction rate is controllable; the solid alkali is adopted, so that the water is prevented from participating in the reaction, the solubility of the inorganic alkali in the organic phase is small, the generation of side reaction can be effectively controlled, and the selectivity and the yield of a target product are improved. After the salt water of the product is dissolved, hydrochloric acid is added to adjust the pH value, and then calcium chloride solution is added into the system to enable fluoride ions to react with calcium chloride to generate calcium fluoride, and the influence of the acid system on equipment is greatly reduced in the process of steaming out the mixture of the product and the water at high temperature due to the small solubility of the calcium fluoride in water. Compared with the traditional method for preparing 5-fluoro-2-nitrophenol by hydrolysis, the method has good technical effect.
Description
Technical Field
The invention relates to the field of organic synthesis, and particularly provides a preparation method of 5-fluoro-2-nitrophenol.
Background
The 5-fluoro-2-nitrophenol is an important intermediate for synthesizing fine chemicals such as the herbicide flumioxazin, and the synthetic route of the intermediate reported in the literature mainly comprises the following steps:
m-fluorophenol nitration:
patent WO2009035407 reports that the method has low industrial value due to the fact that the meta-diphenol is expensive, more side reaction products are produced during nitration, the yield is low, and the separation of the products is difficult.
2, 4-difluoronitrobenzene hydrolysis:
literature 'study on synthesis of novel herbicide flumioxazin' and the like reports that the method carries out hydrolysis reaction on 2, 4-difluoro nitrobenzene through inorganic strong alkali sodium hydroxide, potassium hydroxide and the like, and then acidifies to obtain a target product. The method is easy to operate, and is widely used in the yield. However, the method inevitably generates 25% of byproducts, so that the raw materials cannot be converted into products to the greatest extent, the raw material cost is high, the reaction period is long, and the industrialization is not facilitated.
In order to solve the problem of long reaction period in the pure water system, patent CN110627646A describes that under the condition that alkali, water and an organic solvent exist simultaneously, 2, 4-difluoronitrobenzene is reacted to obtain 5-fluoro-2-nitrophenol.
Amination and hydrolysis of 2, 4-difluoronitrobenzene:
the process is described in patent CN107935858A, where first 2, 4-difluoronitrobenzene is reacted with NH 3 And (3) reacting to obtain 5-fluoro-2-nitroaniline, and then reacting the 5-fluoro-2-nitroaniline under the action of sulfuric acid and sodium nitrite to obtain the 5-fluoro-2-nitrophenol. However, the method is complicated in reaction operation, two steps of reaction are needed to prepare the 5-fluoro-2-nitrophenol, a large amount of acid wastewater is generated, and the industrial application of the method is limited by environmental protection treatment pressure.
Therefore, how to overcome the above-mentioned problems of various preparation techniques is one of the technical problems to be solved in the art.
Disclosure of Invention
The invention provides a preparation method of 5-fluoro-2-nitrophenol aiming at the blank existing in the technology. Aiming at the problems of low yield, high cost and adverse industrialized production of the existing synthesis method, the inventor provides the following solutions: 1) 2, 4-difluoronitrobenzene is used as a starting material, a nonpolar pure organic solvent is selected as a reaction solvent, solid alkali is used as a hydroxylation reagent, the solubility of the solid alkali in an organic phase is small, and the solid alkali is added in batches, so that the generation of impurities can be reduced, and the selectivity and the yield of a target product are improved; because the solubility of the solid alkali in the nonpolar organic solvent is extremely small, dimethyl sulfoxide is added as a cosolvent of the solid alkali, and the forward reaction is promoted. 2) The reaction tracking is that even if the raw materials are remained, the solvent recovery and the application are not affected, and the remained raw materials continue to participate in the reaction along with the solvent recovery and the application; 3) The post-treatment is simple and easy to operate, the reaction is finished, the reaction is directly carried out, the filtrate is directly used (unreacted raw materials continue to react, raw material waste is avoided), after the pH is regulated by the system, the mixture of the directly distilled product and water is kept stand for layering, the separated product is directly quantified, and the cut water (the product with 2-3 points in the water) is directly used in the next batch of acid regulating water; in combination with the three improvements, the final product yield of the invention is improved from 75% to 95-98%. The method has the advantages of good selectivity, small side reaction, high yield, repeated use of solvent and acid regulating water, less three wastes, no need of steam distillation, direct distillation and concentration, energy saving, equipment investment saving, simple operation and easy industrialization.
The specific technical scheme of the invention is as follows:
the preparation method of the 5-fluoro-2-nitrophenol takes 2, 4-difluoronitrobenzene as a raw material and is characterized in that: preparing 5-fluoro-2-nitrophenol by taking a nonpolar organic solvent as a solvent, taking solid alkali as a hydroxylation reagent, and taking dimethyl sulfoxide as a solid alkali cosolvent; the solid alkali is added in batches;
the post-treatment steps are as follows: filtering the reaction system, and leaching filter cake solid salt by adopting the nonpolar organic solvent; dissolving solid salt in water, adding a calcium chloride solution, converting fluoride ions in the system into calcium fluoride precipitates, and regulating the pH value of the system to 2-4; finally, distilling out the product and water, maintaining the temperature above the melting point of the 5-fluoro-2-nitrophenol, wherein the upper layer is a water phase, the lower layer is an organic phase, and separating the lower layer organic phase to obtain the product 5-fluoro-2-nitrophenol.
The specific reaction process of the reaction system is as follows:
2NaF+CaCl 2 →CaF 2 ↓+2NaCl
as a specific embodiment: the molar ratio of the solid alkali to the 2, 4-difluoronitrobenzene is 2-5:1; the mass of the solid alkali cosolvent is 2.5% -11% of the mass of the solid alkali. More preferred embodiments: the molar ratio of the solid alkali to the 2, 4-difluoronitrobenzene is 3-4:1; the mass of the solid alkali cosolvent is 4 to 6 percent of the mass of the solid alkali
As a specific embodiment: the nonpolar organic solvent is one or more of methyl tertiary butyl ether, petroleum ether, toluene, acetonitrile, methylcyclohexane and cyclohexane.
More preferred embodiments: the nonpolar organic solvent is toluene.
As a specific embodiment: the solid alkali is solid sodium hydroxide or solid potassium hydroxide.
As a specific embodiment: the preparation method of the 5-fluoro-2-nitrophenol comprises the following specific steps: dissolving 2, 4-difluoronitrobenzene in a nonpolar organic solvent to prepare a 2, 4-difluoronitrobenzene solution with the mass fraction of 5-30%, adding a solid alkali cosolvent dimethyl sulfoxide, slowly heating to 40-100 ℃, preserving heat for reaction, and adding solid alkali into the system in batches; keeping the temperature and tracking until the residual content of the 2, 4-difluoronitrobenzene is less than or equal to 2wt%. As a more preferred embodiment, the solid base is added in three batches, each batch being separated by a time period of 2 hours.
As a specific embodiment: the temperature of the heat preservation reaction is 60-65 ℃. If the temperature is too low, the reaction is slow, and if the temperature is too high, the impurity content becomes large.
As a specific embodiment: the post-treatment steps specifically include:
a) After the reaction system is qualified by tracking, filtering, eluting filter cake solid salt with toluene with the mass of 12-15% of that of 2, 4-difluoronitrobenzene, and recycling the eluent and filtrate for use in the next batch of reaction solvent;
b) Dissolving solid salt with water of which the mass is 4-7 times that of the solid salt, and adding a calcium chloride solution prepared in advance, wherein the molar ratio of calcium chloride to 2, 4-difluoronitrobenzene is 0.5-1.2:1; dropwise adding hydrochloric acid at 25-30 ℃ to adjust the pH of the system to 2-4;
c) Slowly heating the system after acid adjustment to 120-130 ℃, and distilling out the product and water by adopting a direct distillation mode; the upper layer is water phase, the lower layer is organic product phase, and the two phases are separated by maintaining the temperature above 35 ℃ to obtain the organic product phase.
As a specific embodiment: the mass concentration of the calcium chloride solution in the step c) is 30%.
As a specific embodiment: in step d), after separation of the organic phase product, the remaining aqueous phase contains the product, and this part of the water is directly recycled for use as acid regulating water in the next batch.
And c) directly filtering out solid salt after the reaction liquid in the step a) is tracked to be qualified, directly recycling and applying the filtrate to the next batch of reaction, keeping unreacted raw materials and cosolvent in the solvent at the moment, and continuously participating in the next batch of reaction, wherein the solid salt is a product sodium salt.
In the step b), a certain amount of calcium chloride solution is added into the system before acid regulation, so that sodium fluoride produced by reaction reacts to generate solid calcium fluoride, and the calcium fluoride is very little dissolved in water, thereby reducing the influence of fluoride ions in an acid system on equipment. The molar ratio of the sodium fluoride to the calcium chloride is 1:0.7, and the molar ratio of the sodium fluoride to the calcium chloride is 1:0.7; the mass concentration of the calcium chloride solution is 30%.
In the step c), the product 5-fluoro-2 nitrophenol is liquid at the temperature of more than 35 ℃ and is insoluble in water, two phases can be separated by standing and layering, the content of an organic phase can reach 93-97%, 3-7% of the product is toluene solvent, the part of residual toluene has no influence on the subsequent etherification reaction in which the product participates, the subsequent etherification reaction is carried out under negative pressure for desolventizing, and toluene can be distilled off and cannot enter a solid etherate, so that the product is not removed. After the organic phase product is separated, the residual water phase also contains the product, the content of the product is about 2-3%, and part of water is directly recovered and reused without extraction and is used as the next batch of acid regulating water, so that the operation is simple and the generation of waste water is reduced.
Compared with the prior art, the invention has the main advantages that:
(1) Selecting a nonpolar organic solvent as a reaction solvent, and adopting solid alkali as a hydroxylation reagent; water is prevented from participating in the reaction; the solubility of the solid alkali in the organic phase is small, and the solid alkali is added in batches, so that the generation of side reaction in the solid-liquid two-phase reaction can be effectively controlled, and the selectivity and the yield of the reaction product are improved.
(2) Because the solubility of the solid alkali in the nonpolar organic solvent is extremely small, dimethyl sulfoxide is added as a cosolvent of the solid alkali, and the forward reaction is promoted.
(3) After the reaction tracking is qualified, the filtered organic solvent filtrate can be directly applied to the next batch of reaction solvents without adding cosolvent dimethyl sulfoxide, so that the cosolvent cost loss is reduced.
(4) After the sodium salt or potassium salt of the product is dissolved by using acid regulating water, before the pH value is regulated by adding hydrochloric acid, a calcium chloride solution is added into the system, so that the generated sodium fluoride reacts with calcium chloride to generate calcium fluoride, and the influence of the acid system on equipment is greatly reduced in the process of steaming out the mixture of the product and the water at high temperature due to the small solubility of the calcium fluoride in water.
(5) The water vapor distillation is not used after the acid adjustment, and the distillation concentration method is directly adopted to distill out the mixture of the product and the water, thereby saving energy and equipment investment.
(6) Separating the organic phase from the mixture of the distilled water phase and the organic phase, wherein the content of the product in the water phase is 2-3%, the partial yield is not extracted, the water phase is directly applied to the next batch of acid regulating water, the operation is simple, and the generation of waste water is reduced.
In conclusion, the preparation method disclosed by the invention is simple to operate, high in yield, capable of saving equipment and energy, reusable in solvent, small in environmental pollution, less in three wastes, small in equipment damage, and high in product yield which is more than 95%, and far exceeds the traditional method for preparing 5-fluoro-2-nitrophenol by hydrolysis, so that unexpected technical effects are achieved.
Drawings
FIG. 1 is a liquid-phase diagram of the raw material 2, 4-difluoronitrobenzene used in the present invention,
FIG. 2 is a liquid phase diagram of a reaction trace of the mixed system of alkali + water + dimethyl sulfoxide in comparative example 1,
FIG. 3 is a chart showing the reaction trace liquid phase of the tetrahydrofuran pure solvent system in comparative example 2,
FIG. 4 is a graph showing the trace liquid phase of the pure water system reaction in comparative example 3,
FIG. 5 is a graph showing the reaction trace liquid phase of the pure toluene system used in example 1 of the present invention,
FIG. 6 is a liquid phase diagram of 5-fluoro-2-nitrophenol obtained in the present invention.
Detailed Description
The above-described aspects of the present invention will be described in further detail by way of the following embodiments, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples. All techniques implemented based on the above teachings fall within the scope of the present invention;
example 1
A preparation method of 5-fluoro-2-nitrophenol comprises the following specific steps:
(1) 250g of 2, 4-difluoronitrobenzene toluene solution with the mass fraction of 15% is prepared in a four-necked flask, 1.8160g of dimethyl sulfoxide (the mass of the dimethyl sulfoxide is 5.5% of the mass of sodium hydroxide solid) is added into the system, and the 2, 4-difluoronitrobenzene is prepared according to the following steps: preparing 33.0189g of sodium hydroxide powder according to the molar ratio of sodium hydroxide of 1:3.5, and firstly adding one third of sodium hydroxide powder solid into the system;
(2) Slowly heating the reaction system to 60-65 ℃, keeping the temperature for 2 hours, adding another third of sodium hydroxide solid, keeping the temperature for 2 hours, adding the rest third of sodium hydroxide solid, keeping the temperature for reaction, and keeping the liquid phase tracking the rest of the raw materials to be 0.05% (shown in figure 5);
(3) After the reaction liquid is tracked to be qualified, filtering while the reaction liquid is hot, leaching a filter cake by using 5g of toluene, combining leaching liquor and filtrate, and detecting the residual raw materials in the filtrate;
(4) Adding the filter cake into another four-neck flask, adding 225g of acid regulating water, and stirring to completely dissolve the solid; according to 2, 4-difluoronitrobenzene: 60g of a calcium chloride solution with the mass fraction of 30% prepared in advance is dropwise added into the system according to the molar ratio of calcium chloride of 1:0.7, and then hydrochloric acid is dropwise added to adjust the pH of the system to 3 at the temperature of 25-30 ℃;
(5) After the pH is adjusted, slowly heating the system, starting to distill yellow liquid at the temperature of 120 ℃, stopping distilling until no oil layer is basically distilled, transferring distilled water and oil layer into a separating funnel, separating 35.6g of organic phase oil layer into a charging barrel after the interface of the organic phase oil phase and the upper water phase is separated, detecting the content of toluene as the residual impurity, wherein the yield of the organic phase is 93.2%, the yield of the water phase is 2.2%, the total yield is 95.4%, and the liquid phase spectrum of the product is shown in figure 6.
Examples 2 to 4
Compared with example 1, the other conditions are unchanged, and the reaction conditions of different dimethyl sulfoxide addition amounts (the addition amount% in the table is expressed as the mass ratio of dimethyl sulfoxide to sodium hydroxide solid) are compared, and the result is as follows:
as is clear from examples 1 to 4, the reaction rate is relatively slow when the addition amount of dimethyl sulfoxide is small, so that the reaction time is long, the impurities become large, and the yield is affected; the reaction rate increases when the amount of dimethyl sulfoxide is increased, and the reaction rate does not increase significantly when the amount of dimethyl sulfoxide is further increased, but the impurity becomes large; the final addition of dimethyl sulfoxide was 5.5%.
Examples 5 to 8
Compared with example 1, the other conditions are unchanged, and the reaction conditions of the 2, 4-difluoronitrobenzene toluene solution with different mass fractions (the mass of dimethyl sulfoxide and sodium hydroxide solid are changed in the same proportion with the change of the dosage of the 2, 4-difluoronitrobenzene) are compared, so that the following results are obtained:
from example 1, examples 5 to 8: the concentration of the 2, 4-difluoronitrobenzene toluene solution participating in the reaction is low, the reaction productivity is affected, the concentration is high, the problem of sodium salt sticking to the wall occurs in the reaction process, and the mass transfer and the reaction yield are affected (solid sodium salt aggregation can cause the raw materials to be wrapped inside), so that the yield and the productivity are comprehensively considered, and the concentration of the 2, 4-difluoronitrobenzene is preferably 15%.
Examples 9 to 12
Compared with example 1, other conditions are unchanged, and the reaction conditions of the 2, 4-difluoronitrobenzene at different holding temperatures and the influence of the calcium chloride dosage on the post-treatment are compared, so that the following results are obtained:
the reaction temperature is low, the reaction speed is low, and the reaction time is long, so that the impurity is increased; the heat preservation reaction temperature is high, so that side reactions are larger, the product yield is influenced, and the optimal reaction temperature is 60-65 ℃. The molar ratio of the calcium chloride is low, so that sodium fluoride cannot be fully reacted to generate calcium fluoride, and the molar ratio of the calcium chloride is high, so that raw material waste and solid waste are increased, and 2, 4-difluoronitrobenzene is most preferred: the molar ratio of the calcium chloride is 1:0.7.
Examples 13 to 14
Other conditions were unchanged, the mass of sodium hydroxide varied with the molar ratio, the mass of dimethyl sulfoxide varied with the mass of sodium hydroxide (the mass of dimethyl sulfoxide was always 5.5% of the mass of sodium hydroxide), and the comparison was made with 2, 4-difluoronitrobenzene: the reaction conditions of different molar ratios of sodium hydroxide are as follows:
the molar ratio of sodium hydroxide is low, so that the reaction speed is low, and the impurities grow large due to long reaction time; after the molar ratio of the sodium hydroxide is increased to 3.5, the ratio of the sodium hydroxide is continuously increased, the reaction speed is not obviously increased, the impurities become large, and finally, the ratio of the sodium hydroxide is selected to be 1:3.5.
Example 15
A preparation method of 5-fluoro-2-nitrophenol comprises the following specific steps:
(1) 250g of 2, 4-difluoronitrobenzene toluene solution with the mass fraction of 15% is prepared in a four-necked flask, 1.8160g of dimethyl sulfoxide (the mass of the dimethyl sulfoxide is 5.5% of the mass of sodium hydroxide solid) is added into the system, and the 2, 4-difluoronitrobenzene is prepared according to the following steps: preparing 33.0189g of sodium hydroxide powder according to the molar ratio of sodium hydroxide of 1:3.5, and firstly adding one third of sodium hydroxide powder solid into the system;
(2) Slowly heating the reaction system to 60-65 ℃, keeping the temperature for 2 hours, adding another third of sodium hydroxide solid, keeping the temperature for 2 hours, adding the rest third of sodium hydroxide solid, keeping the temperature for reaction, and keeping the liquid phase tracking the rest of the raw materials to be 0.05%;
(3) After the reaction liquid is tracked to be qualified, filtering while the reaction liquid is hot, leaching a filter cake by using 5g of toluene, combining the leaching liquid and the filtrate, detecting the residual raw materials in the filtrate, and preparing toluene filtrate containing the raw materials to be used in the next batch of reaction solvent;
(4) Adding the filter cake into another four-neck flask, adding 225g of acid regulating water (recycled water containing 5-fluoro-2-nitrophenol and not fully filled with fresh water), and stirring to completely dissolve the solid; according to 2, 4-difluoronitrobenzene: 60g of calcium chloride solution with mass fraction of 30% prepared in advance is dropwise added into the system according to the molar ratio of calcium chloride of 1:0.7, and then hydrochloric acid is dropwise added to adjust the pH of the system to 2-4 at the temperature of 25-30 ℃;
(5) After the pH is regulated, slowly heating the system, starting to evaporate yellow liquid when the temperature is 120 ℃, stopping distilling until no oil layer is substantially evaporated, transferring distilled water and oil layer into a separating funnel, separating an organic phase into a charging barrel after the interface of the organic phase oil phase and the upper water phase is separated, detecting indexes such as content, water content and the like, and sleeving the upper water phase back to the next acid regulating water for use;
(6) Effect of toluene filtrate jacket on reaction:
the toluene filtrate is increased along with the increase of the application times, the water content is increased, so that the reaction tracking impurity is increased, the yield is affected, after the toluene filtrate is recovered and applied for three times, if the toluene filtrate is recovered and applied again, the toluene filtrate is required to be dehydrated, and the reflux water is used for dehydration or the method of adding caustic soda flakes into the toluene filtrate is used for dehydration, so that the dehydration effect is good.
(7) Influence of the number of aqueous phase applications on yield:
after the organic phase and the water phase are separated, the separated water phase can be directly used in the next batch of reaction to be used as acid regulating water, the yield of the product in the water phase is 2-3%, and after the recovery and the application, the total yield of the product is 95-98%, thereby greatly improving the yield of the reaction and the utilization rate of raw materials.
Comparative example 1
This comparative example uses a base, organic solvent, water mixture system to prepare 5-fluoro-2-nitrophenol:
(1) Preparing 196g of 30% potassium hydroxide aqueous solution in a 500ml four-necked flask, adding 55.7g of tetrahydrofuran solvent, and slowly heating the system to 52 ℃;
(2) At the temperature of 52 ℃, 55.7g of 2, 4-difluoronitrobenzene is dripped, the temperature is maintained at 55-58 ℃ in the dripping process, the dripping is completed for 0.5h, the reaction is carried out for 2h after the dripping is completed, the 2, 4-difluoronitrobenzene in the liquid phase is remained for 0.51%, the main peak is 80.3%, the impurity is 19.1%, and the liquid phase tracking spectrum is shown in figure 2;
(3) Adding hydrochloric acid to adjust the pH of the system to 4 at 35 ℃, standing and layering;
(4) The tetrahydrofuran solvent is removed from the organic layer under reduced pressure to obtain 48g of oily product, the detection content is 80.5%, and the yield is 71.7%; the yield of the product in the aqueous phase was 5.6% and the total yield was 77.3%.
The reaction is carried out by using a system of alkali, water and polar organic solvent, the addition of the polar solvent improves the reaction speed and shortens the reaction period, but improves the main reaction speed and the side reaction speed, so that impurities become larger and the yield is influenced; after layering, more products remain in the water phase, the part of products need to be recovered, the solvent is needed to be used for extraction during recovery, then the solvent is removed to obtain the products, the post-treatment operation is complicated, and if the products are not recovered, the waste of the products is caused; the extracted wastewater is acidic and can not be used mechanically, so that a large amount of wastewater is generated.
Comparative example 2
This comparative example uses a pure organic solvent tetrahydrofuran system to prepare 5-fluoro-2-nitrophenol:
adding 32g of raw material 2, 4-difluoronitrobenzene, 32g of tetrahydrofuran and 23.5g of potassium hydroxide solid into a 250ml three-port bottle, heating to 55 ℃, reacting for 2 hours for sampling, tracking the residual content of the 2, 4-difluoronitrobenzene to be 0.03%, tracking the impurity liquid phase to be 15.8%, and obtaining a product liquid phase to be 84.1%, wherein a liquid phase tracking spectrogram is shown in figure 3; cooling the system to 35 ℃, dropwise adding hydrochloric acid to adjust the pH of the system to 4, filtering to remove insoluble inorganic salts and impurities, and then carrying out negative pressure desolventizing on an organic phase to obtain 27.5g of oily product, wherein the impurity liquid phase in the oily product is normalized to 14.7%, the rest of raw materials are normalized to 2.9%, and the product liquid phase is normalized to 82.3%; the oily product was quantified 83.1% and the yield 80.4%.
The phenolic potassium salt generated in the reaction process can not be completely dissolved in tetrahydrofuran, and a blocking phenomenon occurs, so that part of unreacted raw materials are wrapped, and after negative pressure desolventizing, the residual 2.9% of raw materials in the oily product is detected; and the larger lumps present are detrimental to stirring.
The polar solvent is used for reaction, so that the solubility of inorganic alkali in the solvent is improved, the reaction is accelerated, but the contact probability of the alkali and raw materials is increased, and the hydrolysis substitution reaction of fluorine atoms connected to the 4# position is facilitated, so that impurities are generated; the solubility of the generated phenolic potassium salt in the polar solvent is also increased, so that the phenolic potassium salt further reacts to generate disubstituted impurities, thereby influencing the yield and the product quality.
Comparative example 3
This comparative example uses a pure water system to prepare 5-fluoro-2-nitrophenol:
(1) Weighing 32g of 2, 4-difluoronitrobenzene in a 500ml four-necked flask, adding 256g of water, heating and slowly heating to 60-65 ℃;
(2) According to 2, 4-difluoronitrobenzene: the molar ratio of sodium hydroxide is 1:2.4, 77.5g of sodium hydroxide aqueous solution with the mass fraction of 25% is dripped into the system, after the dripping is completed for 1h, the reaction is carried out for 6h, sampling and tracking are carried out until the liquid phase tracking of the raw material is remained by 0.43%, the impurity is normalized to 25.0%, the main peak is 74.5%, and the tracking spectrum is shown in figure 4;
(3) The temperature of the reaction system is reduced to 25-30 ℃ according to the following 2, 4-difluoronitrobenzene: molar ratio of calcium chloride 1:0.7, dropwise adding 51g of calcium chloride solution with mass fraction of 30% prepared in advance into the system, and then dropwise adding hydrochloric acid at 25-30 ℃ to adjust the pH of the system to 2;
(4) After the pH value is regulated, slowly heating the system to 120 ℃, beginning to distill yellow liquid, distilling until an oil-free layer is basically distilled, transferring distilled water and an oil layer into a separating funnel, separating 21g of an organic phase of the oil layer into a charging barrel after the interface of the organic phase and an upper water phase is separated, and conveying and measuring the content and water content;
(5) The detection content is 96.5 percent, and the yield is 65.3 percent; the yield of the product in the aqueous phase was 4.4% and the total yield was 69.7%.
The pure water system is used for reaction, so that the phenomenon of sodium phenolate embracing in the reaction process is avoided to influence the tracking of raw materials, more water is needed to be added, and the amount of waste liquid is increased; because 2, 4-difluoro nitrobenzene is insoluble in water, the reaction is a liquid-liquid two-phase reaction, so the reaction time is longer, the impurity is increased, and the yield is lower.
The comparative examples prove that the product yield is not high when an aqueous system is used for hydrolysis reaction and a pure polar solvent system is used for reaction; the preparation method provided by the invention has the advantages of simple operation, high yield, equipment and energy conservation, repeated use of the solvent, less environmental pollution, less three wastes, less equipment damage and high product yield which is up to more than 95%, and the method is far superior to the traditional method for preparing the 5-fluoro-2-nitrophenol by hydrolysis, and has very excellent technical effects.
Comparative example 4
The procedure of example 1 was repeated except that the dimethyl sulfoxide solid base cosolvent was not added.
A preparation method of 5-fluoro-2-nitrophenol comprises the following specific steps:
(1) Preparing 250g of a 15% 2, 4-difluoronitrobenzene toluene solution in a four-necked flask according to the following weight percentage: preparing 33.0189g of sodium hydroxide powder according to the molar ratio of sodium hydroxide of 1:3.5, and firstly adding one third of sodium hydroxide powder solid into the system;
(2) Slowly heating the reaction system to 60-65 ℃, keeping the temperature for 2 hours, adding another third of sodium hydroxide solid, keeping the temperature for 2 hours, adding the rest third of sodium hydroxide solid, keeping the temperature for 15 hours, and keeping the liquid phase tracking the rest 1.5% of raw materials;
(3) After the reaction liquid is tracked to be qualified, filtering while the reaction liquid is hot, leaching a filter cake by using 5g of toluene, combining leaching liquor and filtrate, and detecting the residual raw materials in the filtrate;
(4) Adding the filter cake into another four-neck flask, adding 225g of acid regulating water, and stirring to completely dissolve the solid; according to 2, 4-difluoronitrobenzene: 60g of a calcium chloride solution with the mass fraction of 30% prepared in advance is dropwise added into the system according to the molar ratio of calcium chloride of 1:0.7, and then hydrochloric acid is dropwise added to adjust the pH of the system to 3 at the temperature of 25-30 ℃;
(5) After the pH is adjusted, slowly heating the system, starting to distill yellow liquid at the temperature of 120 ℃, stopping distilling until no oil layer is basically distilled, transferring distilled water and oil layer into a separating funnel, separating 30.5g of organic phase oil layer into a charging barrel after the interface of the organic phase oil phase and the upper water phase is separated, detecting the content of toluene as the residual impurity, wherein the yield of the organic phase is 80.2%, the yield of the water phase is 2.4%, and the total yield is 82.6%.
The technical features of the above embodiments may be combined in any desired manner, and for brevity, all of the possible combinations of the technical features of the above embodiments may not be described, however, as long as there is no contradiction between the combinations of the technical features, all of which should be considered as being within the scope of the description, the description of the above embodiments may be used to help understand the principles and methods of the present invention. The above embodiments are not intended to be exclusive and should not be construed as limiting the invention. Also, as will be apparent to those of ordinary skill in the art, many modifications, both to specific embodiments and to scope of the invention, are possible in accordance with the principles and methods of the invention.
Claims (10)
1. The preparation method of the 5-fluoro-2-nitrophenol takes 2, 4-difluoronitrobenzene as a raw material and is characterized in that: preparing 5-fluoro-2-nitrophenol by taking a nonpolar organic solvent as a solvent, taking solid alkali as a hydroxylation reagent, and taking dimethyl sulfoxide as a solid alkali cosolvent; wherein the solid base is added in portions;
the post-treatment steps are as follows: filtering the reaction system, and leaching filter cake solid salt by adopting the nonpolar organic solvent; after leaching, dissolving solid salt by adopting water, adding a calcium chloride solution, converting fluoride ions in the system into calcium fluoride precipitates, and adjusting the pH value of the system to 2-4; finally, distilling out the product and water, maintaining the temperature above the melting point of the 5-fluoro-2-nitrophenol, wherein the upper layer is a water phase, the lower layer is an organic phase, and separating the lower layer organic phase to obtain the product 5-fluoro-2-nitrophenol.
2. The method for producing 5-fluoro-2-nitrophenol according to claim 1, wherein the molar ratio of the solid base to 2, 4-difluoronitrobenzene is 2-5:1; the mass of the solid alkali cosolvent is 2.5% -11% of the mass of the solid alkali.
3. The method for producing 5-fluoro-2-nitrophenol according to claim 1, wherein: the nonpolar organic solvent is one or more of methyl tertiary butyl ether, petroleum ether, toluene, acetonitrile, methylcyclohexane and cyclohexane.
4. A process for the preparation of 5-fluoro-2-nitrophenol according to claim 3, wherein: the nonpolar organic solvent is toluene.
5. The method for preparing 5-fluoro-2-nitrophenol according to claim 1, wherein the solid base is solid sodium hydroxide or solid potassium hydroxide.
6. The process for the preparation of 5-fluoro-2-nitrophenol according to any one of claims 1 to 5, comprising the following specific steps: dissolving 2, 4-difluoronitrobenzene in a nonpolar organic solvent to prepare a 2, 4-difluoronitrobenzene solution with the mass fraction of 5-30%, adding a solid alkali cosolvent dimethyl sulfoxide, slowly heating to 40-100 ℃, preserving heat for reaction, and adding solid alkali into the system in batches; keeping the temperature and tracking until the residual content of the 2, 4-difluoronitrobenzene is less than or equal to 2wt%.
7. The method for preparing 5-fluoro-2-nitrophenol according to claim 6, wherein the reaction temperature is 60-65 ℃.
8. The method for producing 5-fluoro-2-nitrophenol according to claim 6, wherein the post-treatment step is specifically:
a) After the reaction system is qualified by tracking, filtering, eluting filter cake solid salt with toluene with the mass of 12-15% of that of 2, 4-difluoronitrobenzene, and recycling the eluent and filtrate for use in the next batch of reaction solvent;
b) Dissolving solid salt with water of which the mass is 4-7 times that of the solid salt, and adding a calcium chloride solution prepared in advance, wherein the molar ratio of calcium chloride to 2, 4-difluoronitrobenzene is 0.5-1.2:1; dropwise adding hydrochloric acid at 25-30 ℃ to adjust the pH of the system to 2-4;
c) Slowly heating the system after acid adjustment to 120-130 ℃, and distilling out the product and water by adopting a direct distillation mode; the upper layer is water phase, the lower layer is organic product phase, and the two phases are separated by maintaining the temperature above 35 ℃ to obtain the organic product phase.
9. The method for producing 5-fluoro-2-nitrophenol according to claim 8, wherein: the mass concentration of the calcium chloride solution in the step c) is 30%.
10. The method for producing 5-fluoro-2-nitrophenol according to claim 8, wherein: in step d), after separation of the organic phase product, the remaining aqueous phase contains the product, and this part of the water is directly recycled for use as acid regulating water in the next batch.
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