CN118791377B - A preparation method of 2,4,5-trifluorophenylacetic acid - Google Patents
A preparation method of 2,4,5-trifluorophenylacetic acid Download PDFInfo
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- CN118791377B CN118791377B CN202411261989.1A CN202411261989A CN118791377B CN 118791377 B CN118791377 B CN 118791377B CN 202411261989 A CN202411261989 A CN 202411261989A CN 118791377 B CN118791377 B CN 118791377B
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- trifluorophenylacetic acid
- trifluorotoluene
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- YSQLGGQUQDTBSL-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=C(F)C=C1F YSQLGGQUQDTBSL-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 46
- ZGEAYXBIJAYBKA-UHFFFAOYSA-N 1,2,4-trifluoro-5-methylbenzene Chemical compound CC1=CC(F)=C(F)C=C1F ZGEAYXBIJAYBKA-UHFFFAOYSA-N 0.000 claims abstract description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 23
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 23
- 238000003756 stirring Methods 0.000 claims abstract description 23
- 239000007787 solid Substances 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 16
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 2,4,5-trifluorophenylacetic acid sodium Chemical compound 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 7
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229940102396 methyl bromide Drugs 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 238000010791 quenching Methods 0.000 claims description 12
- 239000012295 chemical reaction liquid Substances 0.000 claims description 11
- 238000004821 distillation Methods 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- 239000005457 ice water Substances 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 239000007789 gas Substances 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- 238000005935 nucleophilic addition reaction Methods 0.000 description 11
- 230000000171 quenching effect Effects 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 8
- 238000011010 flushing procedure Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 238000005086 pumping Methods 0.000 description 7
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 238000007265 chloromethylation reaction Methods 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- JMXPOOVDUVHJRO-UHFFFAOYSA-N 1-(chloromethyl)-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(CCl)C=C1F JMXPOOVDUVHJRO-UHFFFAOYSA-N 0.000 description 2
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-Bromo-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 description 2
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- ANBBXQWFNXMHLD-UHFFFAOYSA-N aluminum;sodium;oxygen(2-) Chemical compound [O-2].[O-2].[Na+].[Al+3] ANBBXQWFNXMHLD-UHFFFAOYSA-N 0.000 description 2
- 238000005810 carbonylation reaction Methods 0.000 description 2
- IYPQZXRHDNGZEB-UHFFFAOYSA-N cobalt sodium Chemical compound [Na].[Co] IYPQZXRHDNGZEB-UHFFFAOYSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 2
- 229910001388 sodium aluminate Inorganic materials 0.000 description 2
- 229940006198 sodium phenylacetate Drugs 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- RUEXKRNFAABHHU-UHFFFAOYSA-N 5,5,5-trifluoropentanoic acid Chemical compound OC(=O)CCCC(F)(F)F RUEXKRNFAABHHU-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 229910016854 F3 Cl Inorganic materials 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 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 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011684 sodium molybdate Substances 0.000 description 1
- 235000015393 sodium molybdate Nutrition 0.000 description 1
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
- C07C17/269—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions of only halogenated hydrocarbons
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种2,4,5‑三氟苯乙酸的制备方法，涉及有机化工技术领域，1,2,4‑三氟苯中加入三氯化铝，搅拌状态下通入溴甲烷进行反应，得到的2,4,5‑三氟甲苯中继续加入溶剂、氢钠，持续通入二氧化碳，在25‑35℃下反应，得到2,4,5‑三氟苯乙酸钠，经过滤、淬灭，再经30%wt盐酸调节pH至2以下，过滤得到2,4,5‑三氟苯乙酸固体。整个反应过程操作简单，反应条件温和，对环境污染小，适用于工业化生产，且产品的收率和纯度高。
The invention discloses a method for preparing 2,4,5-trifluorophenylacetic acid, and relates to the technical field of organic chemical industry. Aluminum chloride is added to 1,2,4-trifluorobenzene, methyl bromide is introduced under stirring to react, a solvent and sodium hydrogen are continuously added to the obtained 2,4,5-trifluorotoluene, carbon dioxide is continuously introduced, and reacted at 25-35 DEG C to obtain 2,4,5-trifluorophenylacetic acid sodium, filtered, quenched, and then adjusted to pH below 2 with 30%wt hydrochloric acid, and 2,4,5-trifluorophenylacetic acid solid is obtained by filtration. The whole reaction process is simple to operate, the reaction conditions are mild, the environmental pollution is small, it is suitable for industrial production, and the yield and purity of the product are high.
Description
Technical Field
The invention relates to the technical field of organic chemical industry, in particular to a preparation method of 2,4, 5-trifluoro-phenylacetic acid.
Background
2,4, 5-Trifluoro-phenylacetic acid is an important intermediate for synthesizing sitagliptin, and the methods reported in the literature mainly comprise the following steps:
a. The synthesis of 2,4, 5-trifluorobromobenzene into Grignard reagent, coupling with allyl bromide, and oxidizing double bond to obtain 2,4, 5-trifluorophenylacetic acid is disclosed in U.S. Pat. No. 3, 6870067, which discloses a synthesis method of trifluoropropyl acetic acid, wherein 2,4, 5-trifluorobromobenzene is prepared into Grignard reagent, reacted with allyl bromide, and oxidized with periodic acid under catalysis of trichloro nails to obtain 2,4, 5-trifluorophenylacetic acid. However, the Grignard reaction in the method usually adopts low-boiling point volatile solvents such as diethyl ether, is easy to explode, has poor production safety, unstable Grignard reagent and low product yield, and the catalyst ruthenium trichloride and oxidant periodic acid used are expensive, so that the method is not suitable for industrial production.
B. The preparation process of 2,4, 5-trifluoro-phenylacetic acid includes chloromethylating 1,2, 4-trifluoro-benzene to obtain 2,4, 5-trifluoro-benzyl chloride, forming corresponding Grignard reagent, and reacting with carbon dioxide to obtain 2,4, 5-trifluoro-phenylacetic acid, and Chinese patent CN101092345 discloses the preparation process of 2,4, 5-trifluoro-phenylacetic acid, which includes chloromethylating 1,2, 4-trifluoro-benzene to obtain 2,4, 5-trifluoro-benzyl chloride, and reacting with carbon monoxide in the presence of catalyst to obtain 2,4, 5-trifluoro-phenylacetic acid.
C. The preparation method comprises the steps of preparing 2,4, 5-trifluorobenzyl benzene from 1,2, 4-trifluorobenzyl benzene serving as a raw material through chloromethylation reaction of paraformaldehyde/zinc chloride/hydrochloric acid, directly carbonylating the 2,4, 5-trifluorobenzyl benzene under the catalysis of cobalt sodium tetracarbonyl and the action of CO/methanol/NaOH to obtain 2,4, 5-trifluorobenzyl acid, synthesizing 2011,18 (3) and 4-6 in literature, wherein m (C 6H3F3) is 1.0:0.875-0.865 when the 2,4, 5-trifluorobenzyl benzene is prepared from 1,2, 4-trifluorobenzyl acid serving as a raw material through chloromethylation, carbonylation and hydrolysis, and the reaction time is 10 h, and m (C 7H4F3 Cl) is 1:0.275-0.25 when the 2,4, 5-trifluorobenzyl acid is synthesized. Under the condition, the total yield of the product is above 60%, and the mass fraction of the 2,4, 5-trifluoro-phenylacetic acid is above 99%. The method has strong chloromethylation reaction corrosiveness, serious pollution and lower yield. The catalyst of the carbonylation reaction, namely cobalt sodium tetracarbonyl, is high in price and not easy to obtain, and the catalyst and CO are extremely toxic, and the catalyst and CO need pressurizing equipment, so that certain industrialization difficulty exists.
D. Chinese patent CN116730824B discloses a synthesis method of 2,4, 5-trifluoro-phenylacetic acid, which comprises the steps of mixing 1,2, 4-trifluoro-benzene with a catalyst AlCl 3, dropwise adding ethylene oxide liquid at the temperature of 5 ℃, heating to carry out Friedel-crafts alkylation reaction to obtain 2,4, 5-trifluoro-phenylacetic acid, carrying out catalytic reaction on the 2,4, 5-trifluoro-phenylacetic acid and hydrogen peroxide under the catalysis of sodium molybdate to obtain an oxidation product 2,4, 5-trifluoro-phenylacetic acid, filtering the 2,4, 5-trifluoro-phenylacetic acid, adding the filtered 2,4, 5-trifluoro-phenylacetic acid into a sodium hydroxide solution, carrying out heat preservation stirring, cooling the standing liquid, adjusting acid, converting sodium trifluoro-phenylacetate into free acid, crystallizing, filtering and drying to obtain 2,4, 5-trifluoro-phenylacetic acid solid. However, ethylene oxide is inflammable, explosive, toxic and poor in safety, meanwhile, the temperature of Friedel-crafts reaction is 100-120 ℃, the reaction condition is more severe, the selectivity of the polysubstituted Friedel-crafts alkylated impurities is higher, so that the impurities of the product are more, sodium aluminate is used as a catalyst, and the safety is poor.
In summary, the existing preparation method of 2,4, 5-trifluoro phenylacetic acid has the following problems that 1, the prepared intermediate format reagent is unstable, the yield of the final product is about 60%, the reaction yield is low, and the raw materials such as ruthenium trichloride serving as a catalyst and periodic acid serving as an oxidant are expensive. 2. The chloromethylation process has the advantages of strong corrosiveness, more three wastes and the like, and is based on the purposes of improving the reaction yield, reducing the production cost, being good in environmental friendliness and the like.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides the preparation method of the 2,4, 5-trifluoro-phenylacetic acid, which has the advantages of simple operation of the reaction process, high yield and purity of the product and environmental friendliness.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a method for preparing 2,4, 5-trifluoro-phenylacetic acid, comprising the following steps:
Adding aluminum trichloride into 1,2, 4-trifluorobenzene, introducing bromomethane under stirring, heating to 35 ℃ for reaction for 5 hours, washing the reaction feed liquid with sodium carbonate aqueous solution, washing with water to be neutral, and distilling under reduced pressure to obtain 2,4, 5-trifluorotoluene;
The specific reaction equation is:
Adding solvent and sodium hydrogen into 2,4, 5-trifluoro toluene, continuously introducing carbon dioxide, reacting at 25-35 ℃ to obtain 2,4, 5-trifluoro sodium phenylacetate, filtering, quenching, adjusting pH to below 2 by 30%wt hydrochloric acid, and filtering to obtain 2,4, 5-trifluoro sodium phenylacetate solid.
The specific reaction equation is:
Preferably, the molar ratio of 1,2, 4-trifluorobenzene, aluminum trichloride and methyl bromide in step A is 1.67:0.034:0.34.
Preferably, the stirring speed during the reaction in step A is 280-350rpm.
Preferably, the concentration of the aqueous sodium carbonate solution in step A is 5% wt, and the mass ratio of 1,2, 4-trifluorobenzene to the aqueous sodium carbonate solution is 1:0.757w/w.
Preferably, during the reduced pressure distillation in the step A, the fraction at 57-59 ℃ is collected under a vacuum of 15mmHg to obtain 1,2, 4-trifluorobenzene.
Preferably, during the reduced pressure distillation in the step A, the fraction at 70-72 ℃ is collected under a vacuum of 10mmHg to obtain 2,4, 5-benzotrifluoride.
Preferably, the molar ratio of 2,4, 5-benzotrifluoride to sodium hydride in step B is 1:1.1-1.3.
Preferably, the solvent in the step B is one of anhydrous tetrahydrofuran, diethyl ether and isopropyl ether.
Preferably, the volume ratio of the mass of the 2,4, 5-benzotrifluoride to the solvent in the step B is 1:3.42g/mL, and the pressure of the carbon dioxide is maintained at 2MPa during the reaction.
Preferably, the quenching process in the step B is to add the filter cake obtained by filtration into ice water to quench unreacted sodium hydrogen.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
1. The invention uses 1,2, 4-trifluorobenzene as raw materials, does not adopt raw materials with low safety coefficients such as ethylene oxide, sodium aluminate and the like, obtains a final product through three steps of Friedel-crafts alkylation, nucleophilic addition and hydrolysis, has short reaction steps and high purity, has 94.05 percent of Friedel-crafts alkylation reaction yield (calculated by bromomethane), has 85.96-96.71 percent of nucleophilic addition and acidification reaction yield (calculated by 2,4, 5-trifluorotoluene), and improves reaction yield.
2. According to the invention, sodium hydrogen and carbon dioxide are adopted to carry out nucleophilic addition reaction on 2,4, 5-benzotrifluoride to generate sodium 2,4, 5-benzotrifluoride, and hydrochloric acid is adopted to adjust ph to be less than 2, so that a target product is obtained, the whole reaction process is simple to operate, the reaction condition is mild, the environmental pollution is small, and the method is suitable for industrial production.
Drawings
FIG. 1 is a gas chromatogram of 2,4, 5-trifluorotoluene in example 1 of the present invention;
FIG. 2 is a gas chromatogram of 2,4, 5-trifluorophenylacetic acid in example 1 of the present invention;
FIG. 3 is a gas chromatogram of 2,4, 5-trifluorophenylacetic acid in example 2 of the present invention;
FIG. 4 is a gas chromatogram of 2,4, 5-trifluorophenylacetic acid in example 3 of the present invention;
FIG. 5 is a gas chromatogram of 2,4, 5-trifluorophenylacetic acid in example 4 of the present invention;
FIG. 6 is a gas chromatogram of 2,4, 5-trifluorophenylacetic acid in example 5 of the present invention;
FIG. 7 is a gas chromatogram of 2,4, 5-trifluorophenylacetic acid in example 6 of the present invention;
FIG. 8 is a gas chromatogram of 2,4, 5-trifluorophenylacetic acid in example 7 of the present invention;
FIG. 9 is a gas chromatogram of 2,4, 5-trifluorophenylacetic acid in example 8 of the present invention.
Detailed Description
The invention is further illustrated by the following examples.
Example 1
(1) Friedel-crafts alkylation reaction:
660.4g of 1,2, 4-trifluorobenzene and 13.34g of aluminum trichloride are added into a 2L stainless steel reaction kettle, the temperature of the system is reduced to 0 ℃, 94.94g of bromomethane gas is introduced under stirring, the temperature is slowly raised to 35 ℃, the reaction is carried out for 5 hours, 500g of sodium carbonate aqueous solution with the concentration of 5% by weight is added into the reaction liquid, the reaction liquid is pulped for 30 minutes at room temperature, the layers are separated, the organic phase is added with water with the same mass to be washed neutral, then the temperature is raised under the conditions of reduced pressure distillation and vacuum degree of 15mmHg, the fraction at 57-59 ℃ is collected, the fraction is 1,2, 4-trifluorobenzene, the gas phase purity is 99.9% and can be recycled, the residual liquid is raised under the conditions of vacuum degree of 10mmHg, and the fraction at 70-72 ℃ is collected, namely the 2,4, 5-trifluorotoluene, the mass is 137.49, the gas phase purity is 99.95%, and the yield is 94.05% (calculated by bromomethane).
(2) Nucleophilic addition and acidification reactions:
Adding 50mL of anhydrous tetrahydrofuran into a 250mL reaction bottle, adding 14.61g (0.1 mol) of 2,4, 5-benzotrifluoride under stirring, reducing the temperature to 0-5 ℃, adding 2.64g (0.11 mol) of sodium hydride, stirring for 2 hours, transferring the reaction liquid into a 500mL reaction kettle, flushing the material residue in the reaction bottle with 50mL of tetrahydrofuran, taking the reaction kettle into the reaction kettle, vacuumizing, replacing nitrogen for three times, heating to 25 ℃, introducing carbon dioxide to 2MPa, keeping the temperature until the pressure is not reduced, continuing to introduce carbon dioxide to 2MPa after the reaction is not reduced, introducing the reaction for two times, introducing the reaction time for 2 hours, stopping the reaction, reducing the reaction to 20 ℃, filtering, heating the filtrate to 70 ℃, distilling the normal pressure to recover tetrahydrofuran, heating and rectifying the rest liquid under the condition of 10mmHg of vacuum degree, collecting 70-72 ℃ to recover 2,4, 5-benzotrifluoride, slowly quenching the filter cake in 50g of ice water, adjusting the pH value to be less than 2 by 30% by weight of hydrochloric acid, keeping the temperature below 20 ℃, filtering, drying the filtrate to 2, 5-benzotrifluoride content of 2, and drying to 99.95% (based on the solid content of the benzotrifluoride, and GC, and obtaining the solid content of 2.85-95).
Example 2
Varying the amount of sodium hydride used in the nucleophilic addition reaction in step (2) of example 1
Adding 50mL of anhydrous tetrahydrofuran into 200mL of reaction fluorine, adding 14.61g (0.1 mol) of 2,4, 5-trifluoro toluene obtained in the example 1 under stirring, reducing the temperature to 0-5 ℃, adding 2.88g (0.12 mol) of sodium hydride, stirring for 2 hours, transferring the whole reaction liquid into a 500mL reaction kettle, flushing the material residue in the reaction bottle with 50mL of tetrahydrofuran, carrying out vacuum pumping, replacing three times with nitrogen, heating to 40 ℃, introducing carbon dioxide to 2MPa, keeping the temperature for reaction until the pressure is not reduced any more, continuing introducing carbon dioxide to 2MPa, introducing twice, introducing for 2 hours, stopping the reaction, reducing the temperature to 20 ℃, filtering, heating the filtrate to 70 ℃, recovering tetrahydrofuran by normal pressure distillation, heating and rectifying the rest liquid under the vacuum degree of 10mmHg, collecting the fraction of 70-72 ℃, recovering 2,4, 5-trifluoro toluene, slowly adding the filter cake into 50g of ice water for quenching, and then regulating the pH value to be less than 2.6 g by 30% by weight of hydrochloric acid, keeping the pH value under the temperature of 2 ℃ and the temperature of 20 ℃ to 20, and keeping the pH value below 20 ℃ to 2, and obtaining the solid content of trifluoro toluene under the condition of 20, 5-5, and (20.88-20 GC, 20, 5-20 g, and 572.88).
Example 3
Varying the amount of sodium hydride used in the nucleophilic addition reaction in step (2) of example 1
Adding 50mL of anhydrous tetrahydrofuran into a 250mL reaction bottle, adding 14.61g (0.1 mol) of 2,4, 5-trifluoro toluene obtained in the example 1 under stirring, reducing the temperature to 0-5 ℃, adding 3.12g (0.13 mol) of sodium hydride, stirring for 2 hours, transferring the whole reaction liquid into a 500mL reaction kettle, flushing the material residue in the reaction bottle with 50mL of tetrahydrofuran, carrying out vacuum pumping, replacing three times with nitrogen, heating to 25 ℃, introducing carbon dioxide to 2MPa, keeping the temperature for reaction until the pressure is not reduced any more, continuing introducing carbon dioxide to 2MPa, introducing for 2 hours, stopping the reaction, reducing the temperature to 20 ℃, filtering, heating the filtrate to 70 ℃, recovering tetrahydrofuran by normal pressure distillation, heating and rectifying the rest liquid under the vacuum degree of 10mmHg, collecting the fraction of 70-72 ℃ to recover 2,4, 5-trifluoro toluene, slowly adding the filter cake into 50g of ice water for quenching, then adjusting the pH value to be less than 2g by 30%wt hydrochloric acid, keeping the pH value under the temperature of 2 ℃ and keeping the temperature to 2 ℃ at 20 ℃ and the temperature of 2, and keeping the solid content of trifluoro toluene at the temperature of 2-28.89% (2, 28.28 g, 2 GC) and obtaining the solid with the three fluorine-containing three fluorine.
Example 4
Modification of solvent species in nucleophilic addition reaction in step (2) of example 1
Adding 50mL of diethyl ether into a 250mL reaction bottle, adding 14.61g (0.1 mol) of 2,4, 5-trifluoro toluene obtained in the example 1 under stirring, reducing the temperature to 0-5 ℃, adding 2.88g (0.12 mol) of sodium hydride, stirring for 2 hours, transferring the reaction liquid into a 500mL reaction kettle completely, flushing the material residue in the reaction bottle by using 50mL of diethyl ether, carrying out vacuum pumping, nitrogen displacement for three times, heating to 25 ℃, introducing carbon dioxide to 2MPa, keeping the temperature until the pressure is not reduced any more, continuing to introduce carbon dioxide to 2MPa, introducing two times, introducing for 2 hours, stopping the reaction, reducing the temperature to 20 ℃, filtering, heating the filtrate to 70 ℃, distilling the normal pressure to recover diethyl ether, heating and rectifying the residual liquid under the vacuum degree of 10mmHg, collecting 70-72 ℃ to recover 2,4, 5-trifluoro toluene, slowly quenching the filter cake, adjusting the pH value to be less than 2 by using 31.6g of 30% by weight hydrochloric acid, keeping the temperature at 20 ℃ and drying to the temperature of 20 ℃, and obtaining the 2,4, 5-trifluoro toluene with the solid content of which is equal to 16.85% (GC, 16.90-96, 2-96 g, 2-2 GC).
Example 5
Modification of solvent species in nucleophilic addition reaction in step (2) of example 1
Adding 50mL of isopropyl ether into 200mL of reaction fluorine, adding 14.61g (0.1 mol, 146.110) of 2,4, 5-trifluoro toluene obtained in example 1 under stirring, reducing the temperature to 0-5 ℃, adding 2.88g (0.12 mol) of sodium hydride, stirring for 2 hours, transferring the whole reaction liquid into a 500mL reaction kettle, flushing the material residue in the reaction bottle with 50mL of isopropyl ether, carrying out vacuum pumping, replacing three times with nitrogen, heating to 25 ℃, introducing carbon dioxide to 2MPa, keeping the temperature until the pressure is not reduced any more, continuing introducing carbon dioxide to 2MPa, introducing twice, introducing for 2 hours, stopping the reaction, reducing the temperature to 20 ℃, filtering, heating the filtrate to 80 ℃, distilling, recovering the isopropyl ether, rectifying the rest liquid under the condition of 10 ℃ under vacuum, collecting 70-72 ℃ fractions, recovering 2,4, 5-trifluoro toluene, slowly adding the filter cake into 50g of ice water for quenching, then regulating the pH value with 30% by 31.6g of hydrochloric acid to be less than 2 ℃ and keeping the pH value at the temperature of 2 ℃ below 20 ℃ and drying to 20.25% (2, 99.25% of 3, 16%) of benzene, drying to obtain the solid, and obtaining the solid (20.5751%).
Example 6
Changing the reaction temperature of nucleophilic addition in step (2) of example 1
Adding 50mL of anhydrous tetrahydrofuran into 200mL of reaction fluorine, adding 14.61g (0.1 mol) of 2,4, 5-trifluoro toluene obtained in example 1 under stirring, reducing the temperature to 0-5 ℃, adding 2.88g (0.12 mol) of sodium hydride, stirring for 2 hours, transferring the whole reaction liquid into a 500mL reaction kettle, flushing the material residue in the reaction bottle with 50mL of tetrahydrofuran, carrying out vacuum pumping, nitrogen replacement for three times, heating to 30 ℃, introducing carbon dioxide to 2MPa, keeping the temperature for reaction until the pressure is not reduced any more, continuing introducing carbon dioxide to 2MPa, introducing for 2 hours, stopping the reaction, reducing the temperature to 20 ℃, filtering, heating the filtrate to 70 ℃, recovering tetrahydrofuran by normal pressure distillation, heating and rectifying the rest liquid under the vacuum degree of 10mmHg, collecting the fraction of 70-72 ℃ to recover 2,4, 5-trifluoro toluene, slowly adding the filter cake into 50g of ice water for quenching, regulating the pH value to be less than 2g by 30% by weight of hydrochloric acid, keeping the pH value to be less than 2 ℃, keeping the temperature to 2 ℃ and the solid content of benzene at 20 ℃ below 20 ℃ and drying to 99.96%, drying to obtain the solid, and obtaining the solid which is 3.96% (GC, 2.96, 20%).
Example 7
Changing the reaction temperature of nucleophilic addition in step (2) of example 1
Adding 50mL of anhydrous tetrahydrofuran into 200mL of reaction fluorine, adding 14.61g (0.1 mol) of 2,4, 5-trifluoro toluene obtained in example 1 under stirring, reducing the temperature to 0-5 ℃, adding 2.88g (0.12 mol) of sodium hydride, stirring for 2 hours, transferring the reaction liquid into a 500mL reaction kettle completely, flushing the material residue in the reaction bottle with 50mL of tetrahydrofuran, carrying out vacuum pumping, nitrogen replacement for three times, heating to 35 ℃, introducing carbon dioxide to 2MPa, keeping the temperature for reaction until the pressure is not reduced any more, continuing to introduce carbon dioxide to 2MPa, introducing twice, introducing for 2 hours, stopping the reaction, reducing the temperature to 20 ℃, filtering, heating the filtrate to 70 ℃, recovering tetrahydrofuran by normal pressure distillation, heating and rectifying the rest liquid under the vacuum degree of 10mmHg, collecting the fraction of 70-72 ℃, recovering 2,4, 5-trifluoro toluene, slowly adding filter cake into 50g of ice water, quenching unreacted sodium hydride, and then regulating the pH value with 30% by 31.6g to be 2-5-trifluoro toluene, keeping the temperature at the temperature of 2-99 ℃ and drying to obtain the solid, wherein the solid content of benzene is 20.53-20% (20, 20.53-57%).
Example 8
Changing the reaction temperature of nucleophilic addition in step (2) of example 1
Adding 50mL of anhydrous tetrahydrofuran into 200mL of reaction fluorine, adding 14.61g (0.1 mol) of 2,4, 5-trifluoro toluene obtained in example 1 under stirring, reducing the temperature to 0-5 ℃, adding 2.88g (0.12 mol) of sodium hydride, stirring for 2 hours, transferring the whole reaction liquid into a 500mL reaction kettle, flushing the material residue in the reaction bottle with 50mL of tetrahydrofuran, carrying out vacuum pumping, nitrogen replacement for three times, heating to 40 ℃, introducing carbon dioxide to 2MPa, keeping the temperature for reaction until the pressure is not reduced any more, continuing introducing carbon dioxide to 2MPa, introducing for 2 hours, stopping the reaction, reducing the temperature to 20 ℃, filtering, heating the filtrate to 70 ℃, recovering tetrahydrofuran by normal pressure distillation, heating and rectifying the rest liquid under the vacuum degree of 10mmHg, collecting the fraction of 70-72 ℃ to recover 2,4, 5-trifluoro toluene, slowly adding the filter cake into 50g of ice water for quenching, then regulating the pH value to be less than 2 ℃ by 30% by 31.6g of hydrochloric acid, keeping the pH value at the temperature of 2 ℃ below 20 ℃, keeping the pH value at the temperature of 2 ℃ to 2 ℃ and the solid content of 2, drying to 20.90% (GC, drying to 2.90), obtaining the solid, and obtaining the solid with the three-phase, and drying to 2.90% (GC, 2.90%).
It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
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| CN117342925A (en) * | 2023-12-05 | 2024-01-05 | 山东华安新材料有限公司 | Method for continuously preparing 2,4, 6-trifluoro-bromobenzyl |
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