CN116730812A - Preparation method of 4,4' -difluorobenzophenone - Google Patents
Preparation method of 4,4' -difluorobenzophenone Download PDFInfo
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- CN116730812A CN116730812A CN202310630100.1A CN202310630100A CN116730812A CN 116730812 A CN116730812 A CN 116730812A CN 202310630100 A CN202310630100 A CN 202310630100A CN 116730812 A CN116730812 A CN 116730812A
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- Prior art keywords
- magnesium chloride
- difluorobenzophenone
- reaction
- fluorobenzoic acid
- fluorophenyl
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- LSQARZALBDFYQZ-UHFFFAOYSA-N 4,4'-difluorobenzophenone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CC=C(F)C=C1 LSQARZALBDFYQZ-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- ALIGTYPNWJPIKT-UHFFFAOYSA-M [Cl-].FC1=CC=C([Mg+])C=C1 Chemical compound [Cl-].FC1=CC=C([Mg+])C=C1 ALIGTYPNWJPIKT-UHFFFAOYSA-M 0.000 claims abstract description 56
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 50
- -1 4-fluorobenzoic acid magnesium chloride Chemical compound 0.000 claims abstract description 48
- RJCGZNCCVKIBHO-UHFFFAOYSA-N 1-chloro-4-fluorobenzene Chemical compound FC1=CC=C(Cl)C=C1 RJCGZNCCVKIBHO-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 25
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 25
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000011777 magnesium Substances 0.000 claims abstract description 9
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 9
- 239000007858 starting material Substances 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 44
- 239000003960 organic solvent Substances 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000012074 organic phase Substances 0.000 claims description 17
- 238000010438 heat treatment Methods 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000007789 gas Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- 239000002274 desiccant Substances 0.000 claims description 8
- 239000003999 initiator Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 abstract description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 239000000460 chlorine Substances 0.000 abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000004064 recycling Methods 0.000 abstract description 2
- 239000002351 wastewater Substances 0.000 abstract description 2
- 230000008569 process Effects 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 239000007818 Grignard reagent Substances 0.000 description 6
- 150000004795 grignard reagents Chemical class 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 229920001470 polyketone Polymers 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 229930185605 Bisphenol Natural products 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000010587 phase diagram Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JALVMPWRAMMHQY-UHFFFAOYSA-N tris(4-fluorophenyl)methanol Chemical compound C=1C=C(F)C=CC=1C(C=1C=CC(F)=CC=1)(O)C1=CC=C(F)C=C1 JALVMPWRAMMHQY-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- GJMKAUACALCZOM-UHFFFAOYSA-L magnesium;oxolane;dichloride Chemical compound [Mg+2].[Cl-].[Cl-].C1CCOC1 GJMKAUACALCZOM-UHFFFAOYSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Landscapes
- 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
The invention discloses a preparation method of 4,4' -difluorobenzophenone, which comprises the following steps: 4-chloro-fluorobenzene is used as a starting material to react with magnesium scraps to prepare 4-fluorophenyl magnesium chloride; reacting 4-fluorophenyl magnesium chloride with carbon dioxide to prepare 4-fluorobenzoic acid magnesium chloride; reacting 4-fluorophenyl magnesium chloride with 4-fluorobenzoic acid magnesium chloride to prepare 4,4' -difluorobenzophenone. The method has mild reaction conditions, the three-step reaction only needs to carry out post-treatment after the last-step reaction, is simple and convenient to operate, is safe and controllable, does not need to use toxic and harmful reagents such as chlorine or hydrofluoric acid, has high yield, purity and repeatability, and is easy for industrial production; meanwhile, the invention introduces the ketocarbonyl through carbon dioxide, so that the environmental pollution is small, and equipment cannot be corroded; the raw material 4-chlorofluorobenzene can be a waste water recycling byproduct, and the cost is low.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4,4' -difluorobenzophenone.
Background
4,4'-Difluorobenzophenone, english name 4,4' -Difluorobenzophenone, DFBP for short, is an important intermediate applied to medical physiologically active compounds, and is used for synthesizing novel powerful cerebrovascular dilatant fluorobenzeneoxazine and a novel medicine for treating senile dementia. In recent years, with the development of the plastic industry, 4' -difluorobenzophenone as a monomer of an aromatic polyketone polymer is condensed with a large amount of alkali metal double salts of aromatic bisphenol to form various polyketones, and the same bisphenol is condensed into polyketones in the presence of alkali carbonate or bicarbonate, so that the product has wide application prospect.
In recent years, intensive research on the synthesis process of DFBP at home and abroad has been carried out, and numerous processes for synthesizing DFBP have been developed. Methods such as Friedel-crafts reaction, catalytic carbonylation, and fluorination of 4,4' -disubstituted benzophenone can be broadly classified according to the principles of various synthetic routes. However, the existing synthesis methods have some defects, for example, most synthesis methods use toxic and harmful reagents such as chlorine or hydrofluoric acid, and the like, so that the environment is polluted. In addition, the Friedel-crafts reaction method needs to use a large amount of catalysts such as aluminum trichloride, a large amount of hydrogen chloride gas is generated in the reaction and post-treatment processes, the corrosion to production equipment is serious, and the used solvent carbon tetrachloride can cause certain pollution to the environment. The 4,4' -disubstituted benzophenone fluorination process often requires diazotization and also generates a large amount of harmful gases which pollute the environment, and diazonium salts are at risk of explosion.
Thus, there is still a need for further improvements in the current synthetic methods for 4,4' -difluorobenzophenone.
Disclosure of Invention
The invention aims to overcome the technical defects, and provides a preparation method of 4,4'-difluorobenzophenone, which solves the technical problems that in the prior art, toxic and harmful reagents such as chlorine or hydrofluoric acid are required to be used for synthesizing the 4,4' -difluorobenzophenone, the risk is high, the corrosiveness to equipment is large or the environment is polluted.
The invention provides a preparation method of 4,4' -difluorobenzophenone, which comprises the following steps:
4-chloro-fluorobenzene is used as a starting material to react with magnesium scraps to prepare 4-fluorophenyl magnesium chloride;
reacting 4-fluorophenyl magnesium chloride with carbon dioxide to prepare 4-fluorobenzoic acid magnesium chloride;
reacting 4-fluorophenyl magnesium chloride with 4-fluorobenzoic acid magnesium chloride to prepare 4,4' -difluorobenzophenone.
Compared with the prior art, the invention has the beneficial effects that:
the method has mild reaction conditions, the three-step reaction only needs to carry out post-treatment after the last-step reaction, is simple and convenient to operate, is safe and controllable, does not need to use toxic and harmful reagents such as chlorine or hydrofluoric acid, has high yield, purity and repeatability, and is easy for industrial production; meanwhile, the invention introduces the ketocarbonyl through carbon dioxide, so that the environmental pollution is small, and equipment cannot be corroded; the raw material 4-chlorofluorobenzene can be a waste water recycling byproduct, and the cost is low.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 4,4' -difluorobenzophenone prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of 4,4' -difluorobenzophenone prepared in example 1 of the present invention;
FIG. 3 is a liquid phase diagram of 4,4' -difluorobenzophenone produced in example 1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The invention provides a preparation method of 4,4' -difluorobenzophenone, which comprises the following steps:
s1, reacting 4-chlorofluorobenzene serving as a starting material with magnesium scraps to prepare 4-fluorophenyl magnesium chloride;
s2, reacting 4-fluorophenyl magnesium chloride with carbon dioxide to prepare 4-fluorobenzoic acid magnesium chloride;
s3, reacting 4-fluorophenyl magnesium chloride and 4-fluorobenzoic acid magnesium chloride to prepare 4,4' -difluorobenzophenone.
The reaction formula of the invention is as follows:
the traditional Grignard reagent reacts with carbon dioxide, and generally, after the reaction is finished, a dilute acid solution is added for quenching reaction to obtain the carboxylic acid compound. The invention directly uses the Grignard reagent and the product of the carbon dioxide reaction, namely the 4-fluorobenzoic acid magnesium chloride, to continuously react with the Grignard reagent to generate new ketone compounds; compared with the traditional reaction of benzoic acid and Grignard reagent, the method can save the operation of hydrolyzing the magnesium chloride 4-fluorobenzoate into carboxylic acid under the condition of equivalent yield, and has simpler operation.
In the present invention, the possible mechanism of the 3 rd reaction is shown in the following figure. In the process, in the operation process, the 4-fluorophenyl magnesium chloride solution is dropwise added into the 4-fluorobenzoic acid magnesium chloride solution, and the whole reaction process is that the 4-fluorobenzoic acid magnesium chloride is in an excessive condition (a small amount of Grignard reagent) so that no excessive Grignard reagent and product ketone continue to react, thereby controlling the main product in the stage of ketone.
In the above reaction system, if the amount of 4-fluorobenzene magnesium chloride is excessive or the order of addition is changed (the magnesium chloride 4-fluorobenzoate is added dropwise to the magnesium chloride 4-fluorobenzene), the following side reaction may occur, and thus the objective 4,4' -difluorobenzophenone cannot be obtained.
In this embodiment, the step of preparing 4-fluorophenyl magnesium chloride by reacting 4-chlorofluorobenzene as a starting material with magnesium turnings includes: adding 4-chlorofluorobenzene, magnesium scraps and an initiator into a first organic solvent, and carrying out heating reflux reaction to prepare 4-fluorophenyl magnesium chloride. Wherein, the mol ratio of the 4-chlorofluorobenzene to the magnesium turnings is 1: (1 to 3), preferably 1: (1.2-1.5); the initiator is iodine or 1, 2-dibromoethane, and the addition amount of the initiator is 0.1-0.3% of 4-chlorofluorobenzene; the dosage ratio of the 4-chlorofluorobenzene to the first organic solvent is 1g: (2-10) mL, preferably 1g: (3-6) mL; the temperature of the heating reflux reaction is 20-80 ℃, preferably 55-65 ℃; the heating reflux reaction time is 2-6 h, preferably 2-4 h; the reaction atmosphere is nitrogen or argon. In the process, after the reaction is finished, the obtained first organic solvent solution of the 4-fluorophenyl magnesium chloride can be directly used for the subsequent reaction for preparing the 4-fluorobenzoic acid magnesium chloride without an additional separation and purification process.
In this embodiment, the step of reacting 4-fluorophenyl magnesium chloride with carbon dioxide to prepare 4-fluorobenzoic acid magnesium chloride comprises: introducing carbon dioxide gas into the first organic solvent solution of the 4-fluorophenyl magnesium chloride to react to prepare the 4-fluorobenzoic acid magnesium chloride. Wherein, the mol ratio of the 4-fluorophenyl magnesium chloride to the carbon dioxide is 1: (1-3), further 1:2; the reaction temperature of the 4-fluorophenyl magnesium chloride and the carbon dioxide is-50 ℃, and is preferably room temperature; the reaction time is 12-24 h. In the process, after the reaction is finished, the obtained first organic solvent solution of the 4-fluorobenzoic acid magnesium chloride can be directly used for the subsequent reaction for preparing the 4,4' -difluorobenzophenone without an additional separation and purification process.
In this embodiment, the step of reacting 4-fluorophenyl magnesium chloride with 4-fluorobenzoic acid magnesium chloride to prepare 4,4' -difluorobenzophenone comprises: 4,4' -difluorobenzophenone is prepared by reacting 4-fluorophenylmagnesium chloride with 4-fluorobenzoic acid magnesium chloride by slowly dropwise adding a second organic solvent solution of 4-fluorophenylmagnesium chloride to a first organic solvent solution of 4-fluorobenzoic acid magnesium chloride. Wherein, the mol ratio of the 4-fluorobenzoic acid magnesium chloride to the 4-fluorophenyl magnesium chloride is 1: (1 to 1.5), preferably 1: (1 to 1.2), more preferably 1:1.1; the reaction temperature is-80 to 50 ℃, for example, -80 ℃, -70 ℃, -60 ℃, -50 ℃, -40 ℃, -30 ℃, -20 ℃, -10 ℃, 0 ℃, 20 ℃, 50 ℃ and the like, and the invention is not limited thereto; preferably at-80 to-10 ℃, and the reaction time is 4 to 12 hours, preferably 5 to 10 hours; the reaction atmosphere is nitrogen or argon.
In some embodiments of the present invention, after the reaction of the 4-fluorobenzoic acid magnesium chloride and the 4-fluorophenyl magnesium chloride is completed, the method further comprises: slowly adding saturated ammonium chloride aqueous solution into the reaction solution to quench reaction, heating to room temperature, stirring, standing for layering, separating an upper organic phase, and extracting an aqueous phase with ethyl acetate; the organic phases were combined, dried with desiccant, filtered and concentrated under reduced pressure using a rotary evaporator, and the residue was recrystallized to give 4,4' -difluorobenzophenone. Wherein the drying agent is anhydrous sodium sulfate; the solvent used for recrystallization is ethanol.
In this embodiment, the first organic solvent and the second organic solvent are each at least one selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, methylene chloride, n-hexane, and toluene, and preferably tetrahydrofuran. In the present invention, the first organic solvent and the second organic solvent may be the same or different.
In some preferred embodiments of the present invention, the method for preparing 4,4' -difluorobenzophenone as described above comprises the steps of:
adding 4-chlorofluorobenzene, magnesium chips and an initiator into a first organic solvent, and carrying out heating reflux reaction to obtain a first organic solvent solution of 4-fluorophenyl magnesium chloride;
introducing carbon dioxide gas into the first organic solvent solution of the 4-fluorophenyl magnesium chloride for reaction to obtain the first organic solvent solution of the 4-fluorobenzoic acid magnesium chloride;
slowly dripping a second organic solvent solution of 4-fluorophenyl magnesium chloride into a first organic solvent solution of 4-fluorobenzoic acid magnesium chloride to react the 4-fluorophenyl magnesium chloride and the 4-fluorobenzoic acid magnesium chloride, slowly adding a saturated ammonium chloride aqueous solution into the reaction solution to quench the reaction after the reaction is finished, heating to room temperature, stirring, standing for layering, separating an upper organic phase, and extracting a water phase with ethyl acetate; the organic phases were combined, dried with desiccant, filtered and concentrated under reduced pressure using a rotary evaporator, and the residue was recrystallized to give 4,4' -difluorobenzophenone.
Example 1
(1) Preparation of a solution of 4-fluorophenyl magnesium chloride in tetrahydrofuran:
to a 250mL reaction flask was added 2.3g (96 mmol,1.2 eq) of magnesium turnings, 2 elemental iodine (about 20 mg); to 10.4g (80 mmol,1.0 eq) of 4-chlorofluorobenzene was added anhydrous tetrahydrofuran (40 mL), and after mixing well, the mixture was poured into a constant pressure dropping funnel; dropwise adding the 4-chlorofluorobenzene mixed solution (5 mL) into a 250mL reaction bottle under the protection of nitrogen, and heating to 55 ℃, wherein when the color of the reaction solution is changed from brown to colorless, the reaction is initiated; continuously dripping the rest mixed solution at 55 ℃, and controlling the temperature at 55 ℃ to react for 3 hours (only a small amount of magnesium scraps are remained) after dripping is finished; anhydrous tetrahydrofuran is added into the reaction liquid to the total volume of 50mL, and the mixture is stirred uniformly and cooled to room temperature for standby.
(2) Preparation of a solution of magnesium chloride tetrahydrofuran of 4-fluorobenzoic acid:
and (3) introducing carbon dioxide gas into the 4-fluorophenyl magnesium chloride tetrahydrofuran solution obtained in the step (1) at room temperature, evacuating nitrogen of the system, and reacting the reaction solution for 12 hours in a carbon dioxide gas atmosphere. In this process, the consumption of carbon dioxide was 3.5L (160 mmol,2.0 eq).
(3) Preparation of 4,4' -difluorobenzophenone:
introducing nitrogen into the 4-fluorobenzoic acid magnesium chloride tetrahydrofuran solution obtained in the step (2), evacuating carbon dioxide gas of the system, cooling to the temperature of minus 10 ℃, dropwise adding a new 4-fluorobenzene magnesium chloride tetrahydrofuran solution (2.5 mol/L,35mL,1.1 eq), and continuously controlling the temperature of minus 10 ℃ after dripping for stirring for 5 hours; detecting that the peak area of the 4,4' -difluorobenzophenone of the product in the reaction liquid is not increased any more by GC, and stopping the reaction; slowly adding 30mL of saturated ammonium chloride aqueous solution into the reaction solution, quenching the reaction, heating to 25 ℃, stirring for 5 minutes, standing the mixture for layering, separating an upper organic phase, and extracting a water phase by using 50mL multiplied by 2 of ethyl acetate; the organic phases were combined, dried over anhydrous sodium sulfate and the drying agent was filtered off, and the resultant organic phase was concentrated under reduced pressure using a rotary evaporator, and the residue was recrystallized from ethanol to give 14.9g of 4,4' -difluorobenzophenone.
The total yield of the 4,4' -difluorobenzophenone in 3 steps is 85.3 percent based on the 4-chlorofluorobenzene.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 4,4' -difluorobenzophenone. The nuclear magnetic resonance hydrogen spectrum data of 4,4' -difluorobenzophenone are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.89–7.69(m,4H),7.26–7.03(m,4H)。
FIG. 2 is a nuclear magnetic resonance carbon spectrum of 4,4' -difluorobenzophenone. The nmr carbon spectrum data of 4,4' -difluorobenzophenone are as follows: 13 C NMR(101MHz,CDCl 3 )δ193.90,166.78,164.25,133.84,133.81,133.60,132.65,132.57,115.78,115.56。
from the nuclear magnetic resonance spectrum data of FIGS. 1-2, it can be seen that the final product synthesized in the present invention is indeed 4,4' -difluorobenzophenone.
FIG. 3 is a liquid phase diagram of 4,4' -difluorobenzophenone. It can be seen that the purity of the 4,4'-difluorobenzophenone prepared in example 1 of the present invention is 99.92%, which indicates that the 4,4' -difluorobenzophenone synthesized in the present invention has very high purity.
Example 2
The difference from example 1 was only that in step (3), the reaction temperature was 0℃to give 13.8g of 4,4' -difluorobenzophenone.
The total yield of the 4,4' -difluorobenzophenone in 3 steps is 79.0 percent and the purity is 99.95 percent based on the 4-chlorofluorobenzene.
Example 3
The difference from example 1 was only that in step (3), the reaction temperature was 50℃to give 9.5g of 4,4' -difluorobenzophenone.
The total yield of the 4,4' -difluorobenzophenone in 3 steps is 54.4 percent and the purity is 99.88 percent based on the 4-chlorofluorobenzene.
Example 4
The difference from example 1 is only that in step (3), the reaction temperature was-80℃to give 15.1g of 4,4' -difluorobenzophenone.
The total yield of the 4,4' -difluorobenzophenone in 3 steps is 86.5 percent and the purity is 99.95 percent based on the 4-chlorofluorobenzene.
Example 5
The difference from example 1 was only that, in step (3), a new solution of 4-fluorophenyl magnesium chloride in tetrahydrofuran (32 mL,2.5mol/L,1.0 eq) was added dropwise to give 14.4g of 4,4' -difluorobenzophenone.
The total yield of the 4,4' -difluorobenzophenone in 3 steps is 82.5 percent and the purity is 99.60 percent based on the 4-chlorofluorobenzene.
Example 6
The difference from example 1 was that, in step (3), a freshly prepared solution of 4-fluorophenyl magnesium chloride in tetrahydrofuran (48 mL,2.5mol/L,1.5 eq) was added dropwise to give 13.5g of 4,4' -difluorobenzophenone.
The total yield of the 4,4' -difluorobenzophenone in 3 steps is 77.3 percent and the purity is 99.90 percent based on the 4-chlorofluorobenzene.
Comparative example 1
The difference from example 1 was that, in step (3), a new solution of 4-fluorophenyl magnesium chloride in tetrahydrofuran (64 mL,2.5mol/L,2.0 eq) was added dropwise to give 13.2g of 4,4',4 "-trifluorotritanol.
The total yield of 4,4 '-trifluorotrityl alcohol was 52.6% for the 3-step reaction based on 4-chlorofluorobenzene, yielding no 4,4' -difluorobenzophenone.
As is clear from comparative example 1, if the amount of 4-fluorophenyl magnesium chloride used is too large (more than 1.5 equivalents), the excessive 4-fluorophenyl magnesium chloride in the reaction system and the newly produced 4,4'-difluorobenzophenone continue to react to form by-products, and thus 4,4' -difluorobenzophenone cannot be obtained.
Comparative example 2
The difference from example 1 was only that in step (3), the solution obtained in step (2) was added dropwise to a freshly prepared solution of 4-fluorophenyl magnesium chloride in tetrahydrofuran (2.5 mol/L,35mL,1.1 eq) at-10℃to give 10.1g of 4,4',4 "-trifluorotritanol.
The total yield of 4,4 '-trifluorotrityl alcohol was 40.2% for the 3-step reaction based on 4-chlorofluorobenzene, yielding no 4,4' -difluorobenzophenone.
As is clear from comparative example 2, the addition of 4-fluorobenzoic acid magnesium chloride to 4-fluorophenyl magnesium chloride resulted in the fact that the 4-fluorophenyl magnesium chloride was always in an excessive state in the reaction system, and the excessive 4-fluorophenyl magnesium chloride and the newly produced 4,4'-difluorobenzophenone continued to react to form by-products, thereby failing to obtain 4,4' -difluorobenzophenone.
Comparative example 3
(1) The procedure for the preparation of the solution of 4-fluorophenyl magnesium chloride in tetrahydrofuran was as in example 1.
(2) Preparation of 4-fluorobenzoic acid:
introducing carbon dioxide gas into the 4-fluorophenyl magnesium chloride tetrahydrofuran solution obtained in the step (1) at room temperature, evacuating nitrogen of the system, and reacting the reaction solution for 12 hours in the carbon dioxide gas atmosphere; after quenching the reaction with 2M HCl (50 mL), extracted with ethyl acetate (2X 100 mL), the organic phases were combined and concentrated under reduced pressure using a rotary evaporator; the crude product was dissolved in 2M NaOH (200 mL), and washed with diethyl ether (100 mL); concentrated hydrochloric acid is added into the water phase until the pH value is less than or equal to 3, ethyl acetate is used for extraction (3X 100 mL), the organic phases are combined, anhydrous sodium sulfate is dried, suction filtration is carried out, and the filtrate is concentrated under reduced pressure by a rotary evaporator, thus obtaining 10.2g of 4-fluorobenzoic acid with the yield of 91.0%. In this process, the consumption of carbon dioxide was 3.5L (160 mmol,2.0 eq).
(3) Preparation of 4,4' -difluorobenzophenone:
after 4-fluorobenzoic acid (10.2 g,72.8 mmol) obtained in the step (2) is dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to-10 ℃, a new 4-fluorophenyl magnesium chloride tetrahydrofuran solution (2.5 mol/L,35mL,1.1 eq) is added dropwise, and stirring is continued at-10 ℃ for 5 hours after the dropwise addition; detecting that the peak area of the 4,4' -difluorobenzophenone of the product in the reaction liquid is not increased any more by GC, and stopping the reaction; slowly adding 30mL of saturated ammonium chloride aqueous solution into the reaction solution, quenching the reaction, heating to 25 ℃, stirring for 5 minutes, standing the mixture for layering, separating an upper organic phase, and extracting a water phase by using 50mL multiplied by 2 of ethyl acetate; the organic phases were combined, dried over anhydrous sodium sulfate, and after the drying agent was filtered off, the resulting organic phase was concentrated under reduced pressure using a rotary evaporator, and the residue was recrystallized from ethanol to give 14.0g of 4,4' -difluorobenzophenone in a yield of 88.2% and a purity of 99.90%.
The total yield of 4,4' -difluorobenzophenone in 3 steps was 80.3% based on 4-chlorofluorobenzene.
The above-described embodiments of the present invention do not limit the scope of the present invention. Any other corresponding changes and modifications made in accordance with the technical idea of the present invention shall be included in the scope of the claims of the present invention.
Claims (10)
1. The preparation method of the 4,4' -difluorobenzophenone is characterized by comprising the following steps:
4-chloro-fluorobenzene is used as a starting material to react with magnesium scraps to prepare 4-fluorophenyl magnesium chloride;
reacting the 4-fluorophenyl magnesium chloride with carbon dioxide to produce 4-fluorobenzoic acid magnesium chloride;
reacting the 4-fluorophenyl magnesium chloride and the 4-fluorobenzoic acid magnesium chloride to prepare 4,4' -difluorobenzophenone; wherein, the reaction formula is:
2. the method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein the step of preparing 4-fluorophenyl magnesium chloride by reacting 4-chlorofluorobenzene as a starting material with magnesium turnings comprises: adding 4-chlorofluorobenzene, magnesium scraps and an initiator into a first organic solvent, and carrying out heating reflux reaction to prepare 4-fluorophenyl magnesium chloride.
3. The method for preparing 4,4' -difluorobenzophenone according to claim 2, wherein the molar ratio of 4-chlorofluorobenzene to magnesium turnings is 1: (1-3); the initiator is iodine or 1, 2-dibromoethane, and the addition amount of the initiator is 0.1% -0.3% of 4-chlorofluorobenzene; the first organic solvent is at least one selected from tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, methylene dichloride, n-hexane and toluene; the dosage ratio of the 4-chlorofluorobenzene to the first organic solvent is 1g: (2-10) mL; the temperature of the heating reflux reaction is 20-80 ℃; the heating reflux reaction time is 2-6 h; the reaction atmosphere is nitrogen or argon.
4. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein the step of reacting 4-fluorophenyl magnesium chloride with carbon dioxide to prepare 4-fluorobenzoic acid magnesium chloride comprises: introducing carbon dioxide gas into the first organic solvent solution of the 4-fluorophenyl magnesium chloride to react to prepare the 4-fluorobenzoic acid magnesium chloride.
5. The method for preparing 4,4' -difluorobenzophenone according to claim 4, wherein the molar ratio of the 4-fluorophenyl magnesium chloride to the carbon dioxide is 1: (1-3); the reaction temperature of the 4-fluorophenyl magnesium chloride and the carbon dioxide is-50 ℃ and the reaction time is 12-24 h.
6. The method for preparing 4,4'-difluorobenzophenone according to claim 1, wherein the step of reacting 4-fluorophenyl magnesium chloride and 4-fluorobenzoic acid magnesium chloride to prepare 4,4' -difluorobenzophenone comprises: 4,4' -difluorobenzophenone is prepared by reacting 4-fluorophenylmagnesium chloride with 4-fluorobenzoic acid magnesium chloride by slowly dropwise adding a second organic solvent solution of 4-fluorophenylmagnesium chloride to a first organic solvent solution of 4-fluorobenzoic acid magnesium chloride.
7. The method for preparing 4,4' -difluorobenzophenone according to claim 6, wherein the molar ratio of the 4-fluorobenzoic acid magnesium chloride to the 4-fluorophenyl magnesium chloride is 1: (1-1.5); the reaction temperature of the 4-fluorophenyl magnesium chloride and the 4-fluorobenzoic acid magnesium chloride is-80-50 ℃ and the reaction time is 4-12 h; the second organic solvent is selected from at least one of tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, methylene dichloride, n-hexane and toluene; the reaction atmosphere is nitrogen or argon.
8. The method for producing 4,4' -difluorobenzophenone according to claim 1, wherein after the reaction of the 4-fluorobenzoic acid magnesium chloride and the 4-fluorophenyl magnesium chloride is completed, further comprising: slowly adding saturated ammonium chloride aqueous solution into the reaction solution to quench reaction, heating to room temperature, stirring, standing for layering, separating an upper organic phase, and extracting an aqueous phase with ethyl acetate; the organic phases are combined, added with a desiccant for drying, filtered, and the organic phases are concentrated under reduced pressure, and the residues are recrystallized to obtain the 4,4' -difluorobenzophenone.
9. The method for producing 4,4' -difluorobenzophenone according to claim 8, wherein the drying agent is anhydrous sodium sulfate; the solvent used for recrystallization is ethanol.
10. The method for preparing 4,4' -difluorobenzophenone according to claim 1, comprising the steps of:
adding 4-chlorofluorobenzene, magnesium chips and an initiator into a first organic solvent, and carrying out heating reflux reaction to obtain a first organic solvent solution of 4-fluorophenyl magnesium chloride;
introducing carbon dioxide gas into the first organic solvent solution of the 4-fluorophenyl magnesium chloride for reaction to obtain the first organic solvent solution of the 4-fluorobenzoic acid magnesium chloride;
slowly dripping a second organic solvent solution of 4-fluorophenyl magnesium chloride into a first organic solvent solution of 4-fluorobenzoic acid magnesium chloride to react the 4-fluorophenyl magnesium chloride and the 4-fluorobenzoic acid magnesium chloride, slowly adding a saturated ammonium chloride aqueous solution into the reaction solution to quench the reaction after the reaction is finished, heating to room temperature, stirring, standing for layering, separating an upper organic phase, and extracting a water phase with ethyl acetate; the organic phases were combined, dried with desiccant, filtered and concentrated under reduced pressure using a rotary evaporator, and the residue was recrystallized to give 4,4' -difluorobenzophenone.
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