CN114456048A - Preparation method of chlorofluoromethane intermediate - Google Patents
Preparation method of chlorofluoromethane intermediate Download PDFInfo
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- CN114456048A CN114456048A CN202011242459.4A CN202011242459A CN114456048A CN 114456048 A CN114456048 A CN 114456048A CN 202011242459 A CN202011242459 A CN 202011242459A CN 114456048 A CN114456048 A CN 114456048A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- XWCDCDSDNJVCLO-UHFFFAOYSA-N Chlorofluoromethane Chemical compound FCCl XWCDCDSDNJVCLO-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000002994 raw material Substances 0.000 claims abstract description 21
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 19
- 230000008569 process Effects 0.000 claims abstract description 19
- YNCIXVBGKCHARM-UHFFFAOYSA-N 1-(2-methyl-4-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1C YNCIXVBGKCHARM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 238000006266 etherification reaction Methods 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 23
- 239000000543 intermediate Substances 0.000 claims description 23
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 claims description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- -1 amine compounds Chemical class 0.000 claims description 7
- 150000002466 imines Chemical class 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims 1
- 235000011149 sulphuric acid Nutrition 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 6
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000006324 decarbonylation Effects 0.000 abstract description 3
- 238000006606 decarbonylation reaction Methods 0.000 abstract description 3
- 239000002351 wastewater Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000003747 Grignard reaction Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- JERZEQUMJNCPRJ-UHFFFAOYSA-N 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol Chemical compound C=1C=C(OC=2C=CC(Cl)=CC=2)C=C(C(F)(F)F)C=1C(O)(C)CN1C=NC=N1 JERZEQUMJNCPRJ-UHFFFAOYSA-N 0.000 description 1
- XBBGYSIEJHXPLL-UHFFFAOYSA-N 2-bromo-4-fluoro-1-(trifluoromethyl)benzene Chemical compound FC1=CC=C(C(F)(F)F)C(Br)=C1 XBBGYSIEJHXPLL-UHFFFAOYSA-N 0.000 description 1
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 1
- 240000008384 Capsicum annuum var. annuum Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 239000005796 Ipconazole Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 244000037666 field crops Species 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- QTYCMDBMOLSEAM-UHFFFAOYSA-N ipconazole Chemical compound C1=NC=NN1CC1(O)C(C(C)C)CCC1CC1=CC=C(Cl)C=C1 QTYCMDBMOLSEAM-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000005406 washing 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
- C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
Abstract
The invention belongs to the technical field of intermediate compound preparation, and particularly relates to a preparation method of a chlorofluoromethane intermediate. The preparation method of the intermediate of the chlorofluoromethane comprises the steps of taking 4-nitro-2-trifluoromethyl acetophenone as a raw material, and synthesizing through a carbonyl protection reaction, an etherification reaction and a hydrolysis reaction (decarbonylation). The method disclosed by the invention has the advantages of milder reaction conditions, less waste water, easiness in treatment and suitability for industrial large-scale production, and solves the problems of harsh conditions, large quantity of three wastes, harsh production environment and the like in the existing intermediate synthesis line. Moreover, 4-nitro-2-trifluoromethyl acetophenone is used as a raw material, so that the method is suitable for a new synthesis process, greatly reduces the raw material cost for synthesizing the chlorofluoroether oxazole intermediate, and has more practical economic benefits.
Description
Technical Field
The invention belongs to the technical field of intermediate compound preparation, and particularly relates to a preparation method of a chlorofluoromethane intermediate.
Background
Chlorofloxacin (common name: Mefentrifluconazole) is a newly developed epoch-making triazole bactericide of Pasteur, and is formally marketed in 2019. The compound bactericide has the functions of broad spectrum, high efficiency, systemic absorption, eradication, protection and the like, particularly has excellent biological activity on various fungal diseases which are difficult to control, can obviously enhance the control of more than 60 crop diseases, such as field crops of corn, cereal, soybean and the like, economic crops of green pepper, grape and the like, and can also be used for treating lawns, seeds and the like. It has high bioactivity, good environmental properties, low toxicity to mammals and bees, and high safety.
The 4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone is a key intermediate for synthesizing the chlorofluoromethrin, and the chlorofluoromethrin is prepared through epoxidation and ring-opening substitution reaction, and has simple process and high yield. The structure is as follows:
the prior art for producing 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone mostly refers to the art disclosed in the prior art CN103649057A, and 2-bromo-4-fluoro-benzotrifluoride is taken as a raw material, and is subjected to Grignard reaction, acylation reaction, extraction, water washing and other procedures in a tetrahydrofuran solution to prepare 4-fluoro-2-trifluoromethylacetophenone; finally, 4-fluoro-2-trifluoromethyl acetophenone reacts with 4-chlorophenol to synthesize 4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone. The specific process route is as follows:
however, the process route has the following defects: 1. the Grignard reaction is needed, and the conditions are harsh; 2. after the reaction, a large amount of magnesium-containing wastewater is generated and is difficult to treat. In a word, the existing method has the defects of large amount of three wastes, bad production environment and the like when preparing the 4-p-chlorophenoxy acetophenone compounds.
Disclosure of Invention
The invention aims to provide a novel preparation method of a chlorofluoromethane intermediate (4- (4-chlorophenoxy) -2-trifluoromethylacetophenone).
The preparation method of the intermediate of the chlorofluoromethane comprises the steps of taking 4-nitro-2-trifluoromethyl acetophenone as a raw material, and synthesizing through a carbonyl protection reaction, an etherification reaction and a hydrolysis reaction (decarbonylation).
Aiming at the defects of the existing synthesis process of the intermediate of the chlorofluoromethrin, the invention provides a synthesis line of carbonyl protection, etherification and hydrolysis (decarbonylation), which not only omits the Grignard reaction, has milder reaction conditions of the new process, but also has less waste water and easy treatment, is more suitable for industrialized large-scale production, and solves the problems of harsh conditions, large amount of three wastes, bad production environment and the like of the existing synthesis line of the intermediate.
In addition, under the new process framework, a plurality of different raw materials are tried, and 4-nitro-2-trifluoromethylacetophenone is finally screened as a raw material, so that the method is suitable for a new synthesis process, greatly reduces the raw material cost for synthesizing the chlorofluoroether ipconazole intermediate, and has actual economic benefit.
The new synthesis process route of the invention is as follows:
in the formula, R is benzene ring, hydroxyl or C1-C6 alkyl.
In the invention, the carbonyl protection reaction is as follows: under alkaline or acidic conditions, the carbonyl group of 4-nitro-2-trifluoromethylacetophenone (formula II) is protected to produce imine-containing compound of formula (III).
According to acidic and alkaline conditions, the carbonyl protection reaction is divided into two modes:
under alkaline conditions, the carbonyl protection reaction is as follows: hydroxylamine hydrochloride is used for reacting with 4-nitro-2-trifluoromethyl acetophenone to generate imine-containing formula (III). Research shows that the hydroxylamine hydrochloride is selected to react with carbonyl, so that the method has the advantages of more stable raw materials, high yield, less three wastes, simple and convenient operation, environmental protection and the like. If other protective raw materials are replaced, the reaction effect is poor, the yield is low, and even the nitro group after protection is passivated easily to cause the consequence that the nitro group cannot participate in the reaction.
The alkali is any one or combination of sodium hydroxide, potassium carbonate, sodium acetate, sodium methoxide or potassium, sodium ethoxide or potassium, tert-butyl alcohol sodium or potassium and sodium hydrogen; the sodium acetate or sodium hydroxide is preferred, and the method has the advantages of available raw materials, high yield, stable product, high purity and the like.
The amount of the alkali used is 0.8 to 2mol, preferably 0.9 to 1.2mol, relative to 1mol of the compound of formula (II);
under the acidic condition, the carbonyl protection reaction is as follows: amine compounds are reacted with 4-nitro-2-trifluoromethylacetophenone to generate imine-containing compounds of formula (III).
The amine compound refers to branched chain amine such as aniline, benzylamine, isopropylamine, n-butylamine and the like and aromatic cyclic amine, preferably aniline or benzylamine, and has the advantages of strong protection stability, mild reaction, short reaction time, less three wastes, high yield of intermediate products, high purity and the like.
The acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, amino acid or trifluoroacetic acid, preferably p-toluenesulfonic acid or sulfuric acid, and not only is the raw material available, but also the product has good chromaticity and can be recycled; and if the other common acids are replaced, the reaction time is relatively long, the yield is low, and the color intensity is dark.
The amount of the acid is 0.05 to 1.5mol, preferably 0.1 to 1.1mol, relative to 1mol of the compound represented by the formula (II).
In a preferred embodiment of the present invention, the carbonyl protection reaction is performed under acidic conditions, the amine compound is aniline, and the acid is sulfuric acid. Researches show that the reaction purity and yield are high in the group matching mode.
The carbonyl protection reaction is carried out in a solvent, wherein the solvent is one of cyclohexane, toluene, xylene and anisole, and the xylene is preferred.
The etherification reaction is as follows: and (3) etherifying the formula (III) and p-chlorophenol in a polar solvent under the condition of inorganic base to obtain a formula (IV).
The inorganic base is any one of sodium hydroxide, potassium carbonate or sodium carbonate, preferably sodium carbonate or potassium carbonate, the reaction condition is higher, the reaction is more favorable, the generated tar is less, and the obtained product has high yield, high purity and better stability.
The polar solvent is one of acetonitrile, dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.
With respect to 1mol of formula (III), the formula (III): inorganic base: the molar ratio of the p-chlorophenol to the p-chlorophenol is 1: 0.8-2: 0.8 to 2, preferably 0.9 to 1.2mol of inorganic base and 0.9 to 1.1mol of p-chlorophenol.
The reaction temperature is 80-150 ℃, and preferably 110-130 ℃; the time is 2-8h, preferably 3-5 h.
The hydrolysis reaction comprises the following steps: the formula (IV) generates the formula (I) in a solvent under the catalysis of acid water.
The acid is one of hydrochloric acid, sulfuric acid, phosphoric acid and p-toluenesulfonic acid, and hydrochloric acid or sulfuric acid is preferred.
The solvent is one of acetonitrile, dioxane, dichloroethane, cyclohexane, toluene, xylene, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.
The amount of the acid is 0.05 to 0.5mol, preferably 0.1 to 0.2mol, relative to 1mol of the compound represented by the formula (IV).
The reaction temperature is 60-150 ℃, and preferably 70-100 ℃; the time is 5-10h, preferably 6-8.
The invention has the following beneficial effects:
the invention provides a new synthetic route aiming at the defects of the existing process of the intermediate of the chlorofluoromethane. The carbonyl group is protected and then reacts with p-chlorophenol, so that the Grignard reaction can be omitted, and the harsh reaction conditions are avoided; meanwhile, by screening the raw materials, the production cost is greatly reduced, the yield and the purity are improved, and the method has industrial value.
Detailed Description
The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.
The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).
The conversion and selectivity of the reaction are calculated by the following formulas:
conversion rate (molar amount of raw material charged-molar amount of raw material remaining in the product)/molar amount of raw material charged × 100%.
Selectivity ═ actual molar amount of target product/theoretical molar amount of target product × 100%
In the case where no particular mention is made, commercially available products are used as the starting materials.
Example 1
Preparation of 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone
Step 1: in a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 23.7g (0.1mol, 98%) of 4-nitro-2-trifluoromethylacetophenone (formula (I)) and 150mL of xylene as a solvent are added, 11.2g (0.12mol, 99%) of aniline and 5.0g (0.05mol, 98%) of sulfuric acid (catalyst) are added, the mixture is heated, refluxed and stirred for reaction for 6 hours, water generated by the reaction is continuously distilled off, then cooled, and added with water-washed alkali for neutralization and layering, and an organic layer (containing the intermediate product A, formula (II)) is directly subjected to the next reaction. The reaction yield was measured to be 94%.
Step 2: adding the intermediate layer of the reaction product (intermediate A) and 200ml of DMF (solvent) into a four-neck flask provided with a mechanical stirrer, a thermometer and a condenser, adding 12.9g (0.1mol, 99%) of p-chlorophenol (reactant) and 16.6g (0.12mol, 98%) of potassium carbonate (catalyst base), heating to 150 ℃, and detecting the completion of the raw materials by HPLC after 6 hours to obtain a mixture containing the intermediate B and the formula (III);
and step 3: recovering the solvent, adding toluene (solvent) into the mixture containing the intermediate product B, adding acid water (catalyst) to adjust the pH to 7, and separating out the water phase;
adding 0.5g of 50% sulfuric acid (catalyst) solution into an organic phase (containing the intermediate product B), continuously heating to 90 ℃ for hydrolysis reaction for 6 hours, detecting the raw material by HPLC (high performance liquid chromatography), cooling, adding alkali water, standing for layering, and removing toluene from an organic layer to obtain 26.9g of 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone with the content of 98% and the yield of 90%.
Example 2
In contrast to example 1, in step 1: the aniline serving as a protective raw material is replaced by benzylamine, the sulfuric acid is replaced by p-toluenesulfonic acid, other conditions are unchanged, the content of the target product shown in the formula (I) is finally obtained, and the yield is 89%.
Example 3
In contrast to example 1, in step 1: the carbonyl protection reaction is carried out under the alkaline condition, the aniline serving as a protection raw material is replaced by hydroxylamine hydrochloride, the sulfuric acid is replaced by sodium acetate, other conditions are unchanged, the content of the target product shown in the formula (I) is finally obtained, and the yield is 80%.
Example 4
In contrast to example 1, in step 1: the sulfuric acid is changed into p-toluenesulfonic acid, other conditions are unchanged, the content is 98 percent, and the yield is 92 percent.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A preparation method of a chlorofluoromethane intermediate is characterized in that 4-nitro-2-trifluoromethylacetophenone is used as a raw material, and a target product is synthesized through a carbonyl protection reaction, an etherification reaction and a hydrolysis reaction.
2. The process for the preparation of chlorofluoromethrizole intermediates according to claim 1, characterized by the following synthetic route:
wherein R is benzene ring, hydroxyl or C1-C6 alkyl.
3. A process for the preparation of a chlorofluoromethrizole intermediate as claimed in claim 2, wherein the carbonyl protection reaction is: under alkaline or acidic conditions, the carbonyl group of the 4-nitro-2-trifluoromethylacetophenone of the formula (II) is protected to form the imine-containing compound of the formula (III).
4. A process for the preparation of a chlorofluoromethrizole intermediate as claimed in claim 3, wherein the carbonyl protection reaction under basic conditions is: hydroxylamine hydrochloride is used for reacting with 4-nitro-2-trifluoromethyl acetophenone to generate imine-containing formula (III).
5. A process for the preparation of a chlorofluoromethrizole intermediate as claimed in claim 4, wherein the base is sodium acetate or sodium hydroxide.
6. A process for the preparation of a chlorofluoromethrizole intermediate as claimed in claim 3, wherein the carbonyl protection reaction under acidic conditions is: amine compounds are reacted with 4-nitro-2-trifluoromethylacetophenone to generate imine-containing compounds of formula (III).
7. A process for the preparation of a chlorofluoromethrizole intermediate according to claim 6, wherein the amine compound is aniline or benzylamine;
and/or the acid is p-toluenesulfonic acid or sulfuric acid.
8. A process for the preparation of a chlorofluoromethrizole intermediate according to claim 7, wherein the carbonyl protection reaction is carried out under acidic conditions and the amine compound is aniline and the acid is sulphuric acid.
9. A process for the preparation of a chlorofluoromethrizole intermediate as claimed in claim 8, wherein the etherification reaction is: and (3) etherifying the formula (III) and p-chlorophenol in a polar solvent under the condition of inorganic base to obtain a formula (IV).
10. A process for the preparation of a chlorofluoromethrizole intermediate as claimed in claim 9, wherein the inorganic base is sodium or potassium carbonate;
and/or the reaction temperature is 110-130 ℃.
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| CN104230667A (en) * | 2014-09-12 | 2014-12-24 | 王际宽 | Preparation method of R-3, 5-bis (trifluoromethyl) phenyl ethanol |
| CN105829274A (en) * | 2013-12-18 | 2016-08-03 | 巴斯夫农业公司 | Process for the Preparation of Substituted Phenoxyphenyl Ketones |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105829274A (en) * | 2013-12-18 | 2016-08-03 | 巴斯夫农业公司 | Process for the Preparation of Substituted Phenoxyphenyl Ketones |
| CN104230667A (en) * | 2014-09-12 | 2014-12-24 | 王际宽 | Preparation method of R-3, 5-bis (trifluoromethyl) phenyl ethanol |
Non-Patent Citations (1)
| Title |
|---|
| I. A. OS’KINA等: "Kinetics of the Reaction of 1-R-3, 5-Dinitrobenzenes with 4-Chlorophenol in DMF in the Presence of Potassium Carbonate", RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, vol. 46, no. 12, pages 1817 * |
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