CN114456048B - Preparation method of penconazole intermediate - Google Patents
Preparation method of penconazole intermediate Download PDFInfo
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- CN114456048B CN114456048B CN202011242459.4A CN202011242459A CN114456048B CN 114456048 B CN114456048 B CN 114456048B CN 202011242459 A CN202011242459 A CN 202011242459A CN 114456048 B CN114456048 B CN 114456048B
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- WKBPZYKAUNRMKP-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)pentyl]1,2,4-triazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(CCC)CN1C=NC=N1 WKBPZYKAUNRMKP-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 239000005813 Penconazole Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000002994 raw material Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 16
- 230000004224 protection Effects 0.000 claims abstract description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 15
- 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 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000006266 etherification reaction Methods 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 150000002466 imines Chemical class 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 5
- 230000006324 decarbonylation Effects 0.000 abstract description 3
- 238000006606 decarbonylation reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 239000002351 wastewater Substances 0.000 abstract description 3
- 239000005814 Pencycuron Substances 0.000 abstract description 2
- OGYFATSSENRIKG-UHFFFAOYSA-N pencycuron Chemical compound C1=CC(Cl)=CC=C1CN(C(=O)NC=1C=CC=CC=1)C1CCCC1 OGYFATSSENRIKG-UHFFFAOYSA-N 0.000 abstract description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 20
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 6
- 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
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- -1 acetophenone compound Chemical class 0.000 description 5
- 229940090668 parachlorophenol Drugs 0.000 description 5
- 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 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
- 239000003513 alkali Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000013067 intermediate product Substances 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
- 239000002585 base 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
- 239000012074 organic phase Substances 0.000 description 2
- 239000002798 polar solvent 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
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-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
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 1
- 208000003643 Callosities Diseases 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
- 206010020649 Hyperkeratosis Diseases 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
- 239000005592 Penoxsulam Substances 0.000 description 1
- SYJGKVOENHZYMQ-UHFFFAOYSA-N Penoxsulam Chemical compound N1=C2C(OC)=CN=C(OC)N2N=C1NS(=O)(=O)C1=C(OCC(F)F)C=CC=C1C(F)(F)F SYJGKVOENHZYMQ-UHFFFAOYSA-N 0.000 description 1
- 241000219094 Vitaceae Species 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
- 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
- 239000008346 aqueous phase 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
- 238000001514 detection method Methods 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
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 235000021021 grapes Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 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
- 239000000463 material Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 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
- 239000012044 organic layer Substances 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000012216 screening Methods 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
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of intermediate compound preparation, and particularly relates to a preparation method of a penconazole intermediate. The preparation method of the penconazole intermediate takes 4-nitro-2-trifluoromethyl acetophenone as a raw material, and the target product is obtained through carbonyl protection reaction, etherification reaction and hydrolysis reaction (decarbonylation) synthesis. The method has milder reaction conditions, less waste water and easy treatment, is more suitable for industrialized mass production, and solves the problems of harsh conditions, large three wastes, bad production environment and the like of the existing intermediate synthesis line. In addition, the 4-nitro-2-trifluoromethyl acetophenone is used as a raw material, so that the method is not only applicable to a new synthesis process, but also greatly reduces the raw material cost for synthesizing the intermediate of the pencycuron, and has practical economic benefit.
Description
Technical Field
The invention belongs to the technical field of intermediate compound preparation, and particularly relates to a preparation method of a penconazole intermediate.
Background
The penoxsulam (common name: mefenobuconazole) is an epoch-making triazole fungicide newly developed by basf corporation, and is formally marketed in 2019. The plant-type pesticide composition has the functions of broad spectrum, high efficiency, systemic, eradication, protection and the like, particularly has outstanding biological activity on a plurality of fungal diseases which are difficult to control, can obviously strengthen the control of more than 60 crop diseases, such as field crops like corns, grains, soybeans and the like, economic crops like green peppers, grapes and the like, and can also be used for lawn and seed treatment and the like. It has higher bioactivity, good environmental characteristics, low toxicity to mammals, bees and the like, and high safety.
The 4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone is a key intermediate for synthesizing the penconazole, and the penconazole is prepared through epoxidation and ring-opening substitution reaction, so that the process is simple and the yield is higher. The structure is as follows:
the technology used for producing 4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone at present is mostly the technology disclosed in the prior art CN103649057A, wherein 2-bromo-4-fluoro-benzotrifluoride is taken as a raw material, grignard reaction is carried out in tetrahydrofuran solution, then acylation reaction is carried out, and 4-fluoro-2-trifluoromethyl acetophenone is prepared after procedures such as extraction, water washing and the like; 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, this process route has the following drawbacks: 1. the Grignard reaction is needed, and the conditions are more severe; 2. after the reaction, a large amount of magnesium-containing wastewater is generated, which is difficult to treat. In a word, the existing method has the defects of large three wastes, bad production environment and the like when preparing the 4-p-chlorophenoxy acetophenone compound.
Disclosure of Invention
The invention aims to provide a novel preparation method of a penconazole intermediate (4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone).
The preparation method of the penconazole intermediate takes 4-nitro-2-trifluoromethyl acetophenone as a raw material, and the target product is obtained through carbonyl protection reaction, etherification reaction and hydrolysis reaction (decarbonylation) synthesis.
Aiming at the defects of the existing synthesis process of the penconazole intermediate, the invention provides a synthesis line of carbonyl protection-etherification-hydrolysis (decarbonylation), so that the Grignard reaction is omitted, the new process has milder reaction conditions, less waste water and easy treatment, is more suitable for industrialized mass production, and solves the problems of harsh conditions, large three wastes, bad production environment and the like of the existing intermediate synthesis line.
In addition, under the new process frame, we try a plurality of different raw materials, and finally screen 4-nitro-2-trifluoromethyl acetophenone as the raw material, which is not only applicable to the new synthesis process, but also greatly reduces the raw material cost for synthesizing the intermediate of the pencycuron, and has practical economic benefit.
The new synthetic process route of the invention is as follows:
wherein 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-trifluoromethyl acetophenone (formula II) is protected to form imine-containing formula (III).
According to acidic and alkaline conditions, the carbonyl protection reaction is divided into two ways:
under alkaline conditions, the carbonyl protection reaction is as follows: reacting hydroxylamine hydrochloride with 4-nitro-2-trifluoromethyl acetophenone to generate the imine-containing formula (III). Researches show that the hydroxylamine hydrochloride is selected to react with carbonyl, and 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, even the p-nitro passivation after protection is easy to cause, and the reaction cannot be participated.
The alkali is any one or combination of sodium hydroxide, potassium carbonate, sodium acetate, sodium methoxide or potassium, sodium ethoxide or potassium, sodium tert-butoxide or potassium and sodium hydrogen; preferably sodium acetate or sodium hydroxide, has the advantages of available raw materials, high yield, stable product, high purity and the like.
The amount of the base to be used is 0.8 to 2mol, preferably 0.9 to 1.2mol, relative to 1mol of the compound of formula (II);
under acidic conditions, the carbonyl protection reaction is as follows: the amine compound is reacted with 4-nitro-2-trifluoromethyl acetophenone to generate the imine-containing formula (III).
The amine compound refers to branched chain amine and aromatic ring amine such as aniline, benzylamine, isopropylamine, n-butylamine, and the like, and preferably aniline or benzylamine, and has the advantages of strong protection stability, mild reaction, short reaction time, less three wastes, high intermediate product yield, 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 the raw materials are available, and the product has good chromaticity and can be recycled; if the acid is replaced by other common acid, the reaction time is relatively long, the yield is low, and the chromaticity is deep.
The amount of the acid to be used is 0.05 to 1.5mol, preferably 0.1 to 1.1mol, relative to 1mol of the compound represented by the formula (II).
As one of the preferred embodiments of the present invention, the carbonyl-protecting reaction is performed under acidic conditions, and the amine compound is aniline, and the acid is sulfuric acid. The research shows that the combination mode has higher reaction purity and yield.
The carbonyl protection reaction is carried out in a solvent, wherein the solvent is one of cyclohexane, toluene, xylene and anisole, and preferably xylene.
The etherification reaction is as follows: under the condition of inorganic alkali, the formula (III) and parachlorophenol are etherified in a polar solvent to obtain the 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 more temperature, 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.
The formula (III) is described with respect to 1mol of formula (III): inorganic base: the molar ratio of the parachlorophenol 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 parachlorophenol.
The reaction temperature is 80-150 ℃, preferably 110-130 ℃; the time is 2-8 hours, preferably 3-5 hours.
The hydrolysis reaction is as follows: the acid water catalysis is used for generating the formula (I) in a solvent.
The acid is one of hydrochloric acid, sulfuric acid, phosphoric acid and p-toluenesulfonic acid, preferably hydrochloric acid or sulfuric acid.
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 to be used 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 ℃, preferably 70-100 ℃; the time is 5-10h, preferably 6-8.
The beneficial effects of the invention are as follows:
aiming at the defects of the prior art of the intermediate of the penconazole, the invention provides a new synthetic route. The protected carbonyl is reacted with parachlorophenol, so that Grignard reaction can be omitted, and harsh reaction conditions are avoided; meanwhile, through 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 illustrative of the invention and 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 were calculated by the following formula:
conversion= (molar amount of raw material charged-molar amount of raw material remaining in product)/molar amount of raw material charged x 100%.
Selectivity = actual molar amount of target product/theoretical molar amount of target product x 100%
Unless otherwise specified, all materials used are commercially available products.
Example 1
Preparation of 4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone
Step 1: in a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 23.7g (0.1 mol, 98%) of 4-nitro-2-trifluoromethyl acetophenone (formula (I)) and 150mL of solvent xylene were added, followed by 11.2g (0.12 mol, 99%) of aniline and 5.0g (0.05 mol, 98%) of sulfuric acid (catalyst), the reaction was heated, refluxed and stirred for 6 hours, water produced in the reaction was continuously distilled off, then cooled, and then added with water washing alkali to neutralize and delaminate, and the organic layer (containing intermediate product A formula (II)) was directly removed for the next reaction. The reaction yield was 94% as measured.
Step 2: in a four-necked flask equipped with mechanical stirring, thermometer and condenser, the intermediate layer of the above reaction product (intermediate A) and 200ml of DMF (solvent) were added, followed by addition of 12.9g (0.1 mol, 99%) of parachlorophenol (reactant) and 16.6g (0.12 mol, 98%) of potassium carbonate (catalyst base), followed by heating to 150℃and after 6 hours HPLC detection of complete starting material to give a mixture containing intermediate B of formula (III);
step 3: after recovering the solvent, toluene (solvent) is added to the mixture containing intermediate B, acid water (catalyst) is added to adjust ph=7, and the aqueous phase is separated;
adding 0.5g of 50% sulfuric acid (catalyst) solution into an organic phase (containing an intermediate product B), continuously heating to 90 ℃ for hydrolysis reaction for 6 hours, detecting the raw materials completely by HPLC, cooling, adding alkaline water for neutralization, standing and layering, and removing toluene from the organic phase to obtain 26.9g of 4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone, wherein the content is 98%, and the yield is 90%.
Example 2
Unlike 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, and the content of a target product shown in a formula (I) is finally obtained with the yield of 89%.
Example 3
Unlike example 1, in step 1: the carbonyl protection reaction is carried out under alkaline condition, the aniline as the protection raw material is replaced by hydroxylamine hydrochloride, the sulfuric acid is replaced by sodium acetate, and other conditions are unchanged, so that the content of the target product shown in the formula (I) is finally obtained with the yield of 80%.
Example 4
Unlike example 1, in step 1: the sulfuric acid is changed into p-toluenesulfonic acid, other conditions are unchanged, the content is 98%, and the yield is 92%.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (2)
1. The preparation method of the penconazole intermediate is characterized in that 4-nitro-2-trifluoromethyl acetophenone is taken as a raw material, and a target product is synthesized through carbonyl protection reaction, etherification reaction and hydrolysis reaction; the synthetic route is as follows:
wherein R is hydroxy;
the carbonyl protection reaction is as follows: under alkaline conditions, the carbonyl protection reaction is as follows: reacting hydroxylamine hydrochloride with 4-nitro-2-trifluoromethyl acetophenone to generate the imine-containing formula (III).
2. The method for preparing a penconazole intermediate according to claim 1, wherein said base is sodium acetate or sodium hydroxide.
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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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| 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 |
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| 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.2010,第第46卷卷(第第12期期),第1817–1821页. * |
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